Method for synthesis of substituted azole libraries

ABSTRACT

The invention relates to methods of synthesizing libraries of diverse and complex 2-substituted azole compounds of the general formula (I) or (II)  
                 
 
     wherein X, R 2  and the ring components  
                 
 
     are as described herein, novel intermediates useful for synthesizing such substituted azole compounds and methods for identifying and isolating the compounds.

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims the priority of U.S. provisionalapplication Ser. No. 60/209,252 filed Jun. 5, 2000, the contents ofwhich are hereby incorporated by reference.

FIELD OF THE INVENTION

[0002] The present invention is directed to a method of synthesizinglibraries of diverse and complex 2-substituted azole derivatives andnovel intermediate compounds.

BACKGROUND OF THE INVENTION

[0003] Compounds having biological activity can be identified byscreening diverse collections of compounds (i.e., libraries ofcompounds) produced through synthetic chemical techniques.

[0004] The generation of chemical libraries on and off solid resins haveproven to be a valuable resource for the pharmaceutical industry intheir endeavors to discover new drugs using high throughput screening(HTS) techniques. In creating the libraries, the compounds are ideallysynthesized in situ in solution phase or on a solid support. However,relatively simple synthetic methods to produce a diverse collection ofsuch derivatives in situ are often not available.

[0005] Such screening methods include methods wherein each member of thelibrary is tagged with a unique identifier tag to facilitateidentification of compounds having biological activity or where thelibrary comprises a plurality of compounds synthesized at specificlocations on the surface of a solid substrate wherein a receptor isappropriately labeled to identify binding to the compound, e.g.,fluorescent or radioactive labels. Correlation of the labeled receptorbound to the substrate with its location on the substrate identifies thebinding compound. Using these techniques, the development of efficienthigh throughput screening has greatly enhanced the pharmaceuticalindustry's ability to screen large numbers of compounds for biologicalactivity. Central to these methods is the screening of a multiplicity ofcompounds in the library and the ability to identify the structures ofthe compounds that have a requisite biological activity.

[0006] Pharmaceutical drug discovery relies heavily on studies ofstructure-activity relationships wherein the structure of “leadcompounds” is typically altered to determine the effect of suchalteration on activity. Alteration of the structure of the leadcompounds permits evaluation of the effect of the structural alterationon activity.

[0007] Thus, libraries of compounds derived from a lead compound can becreated by including derivatives of the lead compound and repeating thescreening procedures. In this manner, compounds with the best biologicalprofile, i.e., those that are most active and which have the most idealpharmacologic and pharmacokinetic properties, can be identified from theinitial lead compound.

[0008] Recently, 2-substituted oxazoles were found to be potent as MMPinhibitors (Sheppard, et al, in Bioorg Med Chem Lett 8(22), 3251(1998)); 2-substituted imidazoles were found to produce local anestheticeffects (Colombo, et al., Rev Farmacol Clin Exp, 4(1), 41-47 (1987); and2-substituted thiazoles were found to be selective inhibitors of5-lipoxygenase (Bird, et al., 5^(th) Int Conf Inflamm Res Assoc (Sept23-27 Whit Haven) Abst 85, 1990).

[0009] Synthesis of substituted nitrogen containing heteroaryls usingsolution phase chemistry has been previously described. Khristich etal., in Khimia Geterotsiklicheskikh Soedineii, 8, 1136-36 (1983)describe the solution phase synthesis ofα-(1-methyl-2-benzimidazolyl)benzyl benzoates. Roe et al., in JCS p 2195(1963) describe the thermal condensation of imidazoles with carbonylcompounds. Papadopolous, in J. Org. Chem., 42 (24) 3925-29, (1977)describes reaction of imidazoles with isocyanates, while Papadopolous etal., in J. Org. Chem., 44(1) 99-104 (1979) describe reactions of azoleswith isocyanates. Cleavage of the silicon-carbon bond of2-trimethylsilyl-1-methylimidazole and 2-trimethylsilyl-1-benzimidazoleto yield 2-substituted imidazoles and 2-substituted benzimidazoles isdescribed by Pinkerton, F. H. and Thames, S. F., in J. Heterocycl. Chem.9(1), 67-72 (1972). Dondoni et al., in J. Org. Chem., 53, 1748-61 (1988)describe the synthesis of (trimethylsilyl)thiazoles which are reactedwith carbonyl compounds to prepared highly substituted thiazoles.

[0010] In order to develop new pharmaceutical drugs to treat variousdisease conditions, it would be highly desirable to be able to generatesuch libraries of substituted azole derivatives and novel intermediatecompounds. Thus, there is a need for a facile in situ method for thegeneration of a multiplicity of substituted azole derivatives and novelintermediate compounds.

SUMMARY OF THE INVENTION

[0011] The present invention is directed to a process for assembly ofdiverse, 2-substituted azole derivatives and novel intermediatecompounds using available azoles as starting materials. The rapidsynthesis of such highly complex drug-like molecules is unexpected andsurprising.

[0012] Accordingly, the invention is directed to a method ofsynthesizing 2-substituted azole derivatives having the formula (I) or(II):

[0013] wherein

[0014] X is selected from the group consisting of NH, NRA, and S;

[0015] X represents a 5 membered aromatic ring structure; optionallycontaining one to two additional heteroatoms selected from the groupconsisting of N, O and S;

[0016] provided that the additional heteroatoms are not at theattachment point of the R² group (i.e. the R² group is always attachedto a ring carbon);

[0017] provided that the 5 membered ring remains aromatic in nature;

[0018] wherein the 5 membered ring is optionally substituted with one tothree substituents independently selected from the group consisting ofhalogen, hydroxy, alkyl, alkenyl, halogenated alkyl, cycloalkyl, alkoxy,aryl, aralkyl, heterocyclyl, amino, mono-or di-substituted amino, cyano, nitro, —COOR,— COR, —SO₂R, —CONR^(B)R^(C); wherein the aminesubstituents are independently selected from alkyl, cycloalkyl, aryl oraralkyl; wherein the cycloalkyl, aryl or heterocyclyl may be furtheroptionally substituted with one or more substituent is independentlyselected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino,mono-or di-substituted amino, cyano or nitro;

[0019]

[0020] represents a 9 membered ring structure, wherein the five memberedportion of the ring structure

[0021] is aromatic and the six membered portion of the ring structure

[0022] is saturated, partially unsaturated, or aromatic;

[0023] wherein the 5 membered portion of the ring structure isoptionally substituted with one to two substituents independentlyselected from the group consisting of halogen, hydroxy, alkyl, alkenyl,halogenated alkyl, cycloalkyl, alkoxy, aryl, aralkyl, heterocyclyl,amino, mono-or di-substituted amino, cyano, nitro, —COOR, —COR, —SO₂Rand —CONR^(B)R^(C); wherein the amine substituents are independentlyselected from alkyl, cycloalkyl, aryl or aralkyl; wherein thecycloalkyl, aryl or heterocyclyl may be further optionally substitutedwith one or more substituent is independently selected from halogen,hydroxy, alkyl, halogenated alkyl, alkoxy, amino, mono-or di-substitutedamino, cyano or nitro;

[0024] wherein the 6-membered portion of the ring structure may furtheroptionally containing one to four additional heteroatoms selected fromthe group consisting of N, O and S;

[0025] wherein the 6-membered portion of the ring structure may furtherbe optionally substituted with one to four substituents independentlyselected from the group consisting of halogen, hydroxy, alkyl,halogenated alkyl, cycloalkyl, alkoxy, aryl, aralkyl, heterocyclyl,amino, mono-or di-substituted amino, cyano, nitro, —COOR, —COR, —SO₂Rand —CONR^(B)R^(C); wherein the amine substituents are independentlyselected from alkyl, cycloalkyl, aryl or aralkyl; wherein thecycloalkyl, aryl or heterocyclyl may be further optionally substitutedwith one or more substituent independently selected from halogen,hydroxy, alkyl, halogenated alkyl, alkoxy, amino, mono-or di-substitutedamino, cyano or nitro;

[0026] R² is selected from the group consisting of

[0027] Z is selected from the group consisting of hydrogen, —OR^(A),—NR^(A)R^(B),— N(R^(A))ORB, —SR, —CN, —N₃, and

wherein

[0028] N represents a three to eight membered heterocyclyl group boundat the N atom, wherein the heterocyclyl group is saturated, partiallyunsaturated or aromatic; when the heterocyclyl group is a saturated sixto eight membered heterocyclyl, the heterocyclyl group may optionallycontains a group selected from O, CHR, NR, S, SO, or SO₂, provided thatthat the group is separated from the N atom by at least two carbonatoms; adn wherein the heterocyclyl group is optionally substituted withone or more substituents independently selected from R;

[0029] R³ is selected from the group consisting of hydrogen, alkyl,aralkyl, cycloalkyl, fluorinated alkyl, —COR, —COOR and —CONR^(C)R^(D);wherein the aralkyl may be optionally substituted with one or moresubstituents independently selected from halogen, hydroxy, alkyl,halogenated alkyl, alkoxy, amino, mono- or di-substituted amino, cyanoor nitro;

[0030] R⁴ is selected from the group consisting of alkyl, aryl, aralkyl,cycloalkyl, fluorinated alkyl, alkenyl, alkynyl, —COOR, —COR,—CONR^(C)R^(D) , -alkyl—COOR, heterocycle and

[0031] wherein the alkyl, alkenyl, alkynyl, aryl, aralkyl or heterocyclemay be optionally substituted with one or more substituentsindependently selected from halogen, hydroxy, alkyl, halogenated alkyl,alkoxy, aryl, amino, mono-or di-substituted amino, cyano or nitro;wherein Y is selected from the group consisting of O, S and NRA;

[0032] R⁵ is selected from the group consisting of hydrogen, alkyl,aryl, aralkyl, cycloalkyl, fluorinated alkyl and heterocycle; whereinthe aryl, aralkyl or heterocycle may be optionally substituted with oneor more substituents independently selected from halogen, hydroxy,alkyl, halogenated alkyl, alkoxy, amino, mono-or di-substituted amino,cyano or nitro;

[0033] R⁶ is selected from the group consisting of hydrogen, alkyl,aralkyl, cycloalkyl, —COOR, —COR, —SO₂R, —CONR^(C)R^(D) and

[0034] where R is selected from the group consisting of alkyl, aryl,aralkyl, cycloalkyl, adamantyl, norbornyl, fluorinated alkyl andheterocycle; wherein the aryl, aralkyl or heterocycle may be optionallysubstituted with one or more substituents independently selected fromhalogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino, mono-ordi-substituted amino, cyano or nitro;

[0035] where R^(A) and R^(B) are independently selected from the groupconsisting of hydrogen, —R, —COOR, —COR, —SO₂R, —SOR and —CONR^(C)R^(D)and

[0036] where R^(C) and R^(D) are independently selected from the groupconsisting of hydrogen, alkyl, aryl, aralkyl, cycloalkyl, fluorinatedalkyl and heterocycle; wherein the aryl, aralkyl or heterocycle may beoptionally substituted with one or more substituents independentlyselected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino,mono-or di-substituted amino, cyano or nitro; or are joined together toform a 4 to 8 membered heterocyclyl ring structure;

[0037] and pharmaceutically acceptable salt, esters and pro-drugsthereof;

[0038] by a facile reaction of an azole compound with a carbamylchloride followed by reaction in situ with an aldehyde or isocyanate toyield the desired 2-substituted azole.

[0039] More particularly, the present invention is directed to a processfor preparing compound of the formula (Ia)

[0040] wherein

[0041] X is selected from the group consisting of NH, NR^(A), and S;

[0042]

[0043] represents a 5 membered aromatic ring structure; optionallycontaining one to two additional heteroatoms selected from the groupconsisting of N, O and S;

[0044] provided that the additional heteroatoms are not at theattachment point of the

[0045] group;

[0046] provided that the 5 membered ring remains aromatic in nature;

[0047] wherein the 5 membered ring is optionally substituted with one tothree substituents independently selected from the group consisting ofhalogen, hydroxy, alkyl, halogenated alkyl, alkenyl, cycloalkyl, alkoxy,aryl, aralkyl, heterocyclyl, amino, mono-or di-substituted amino, cyano,nitro, —COOR,— COR, —SO₂ and —CONR^(B)R^(C); wherein the aminesubstituents are independently selected from alkyl, cycloalkyl, aryl oraralkyl; wherein the cycloalkyl, aryl or heterocyclyl may be furtheroptionally substituted with one or more substituent is independentlyselected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino,mono-or di-substituted amino, cyano or nitro;

[0048] Z is selected from the group consisting of hydrogen, —OR^(A),—NR^(A) R^(B), —SR, —N(R^(A))OR^(B), —CN, —N₃ and;

[0049] wherein

represents a three to eight membered heterocyclyl group bound at the Natom, wherein the heterocyclyl group is saturated, partially unsaturatedor aromatic; when the heterocyclyl group is a saturated six to eightmembered heterocyclyl, the heterocyclyl group may optionally contains agroup selected from O, CHR, NR, S, SO, or SO₂, provided that that thegroup is separated from the N atom by at least two carbon atoms; adnwherein the heterocyclyl group is optionally substituted with one ormore substituents independently selected from R;

[0050] R³ is selected from the group consisting of hydrogen, alkyl,aralkyl, cycloalkyl, fluorinated alkyl, —COR, —COOR and —CONR^(C)R^(D);wherein the aralkyl may be optionally substituted with one or moresubstituents independently selected from halogen, hydroxy, alkyl,halogenated alkyl, alkoxy, amino, mono- or di-substituted amino, cyanoor nitro;

[0051] R⁴ is selected from the group consisting of alkyl, aryl, aralkyl,cycloalkyl, fluorinated alkyl, alkenyl, alkynyl, —COOR, —COR,—CONR^(C)R^(D), -alkyl—COOR, heterocyclyl and

[0052] wherein the alkyl, alkenyl, alkynyl, aryl, aralkyl orheterocyclyl may be optionally substituted with one or more substituentsindependently selected from halogen, hydroxy, alkyl, halogenated alkyl,alkoxy, aryl, amino, mono-or di-substituted amino, cyano or nitro; andwhere Y is selected from the group consisting of O, S and NR^(A);

[0053] where R is selected from the group consisting of alkyl, aryl,aralkyl, cycloalkyl, adamantyl, norbornyl, fluorinated alkyl andheterocycle; wherein the aryl, aralkyl or heterocycle may be optionallysubstituted with one or more substituents independently selected fromhalogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino, mono-ordi-substituted amino, cyano or nitro;

[0054] where R^(A) and R^(B) are independently selected from the groupconsisting of hydrogen, —R, —COOR, —COR, —SO₂R, —SOR and —CONR^(C)R^(D)and

[0055] where R^(C) and R^(D) are independently selected from the groupconsisting of hydrogen, alkyl, aryl, aralkyl, cycloalkyl, fluorinatedalkyl and heterocycle; wherein the aryl, aralkyl or heterocycle may beoptionally substituted with one or more substituents independentlyselected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino,mono-or di-substituted amino, cyano or nitro; or are joined together toform a 4 to 8 membered heterocyclyl ring structure;

[0056] which method comprises reacting a compound of formula (III)

[0057] with a compound of formula (IV)

[0058] wherein A is selected from F, Cl, Br, and —OC(O)-t-butyl andwherein V is a sterically hindered group, in a non-protic solvent;

[0059] and then reacting with a compound of formula (V)

[0060] wherein W is selected from the group consisting of —O, —NSO₂R,—NSOR, —NCOR, —NCOOR, NCONRCR^(D), —NOCOR and —NR, to form thecorresponding compound of formula (Ic)

[0061] and optionally reacting the compound of formula (Ic) with acompound of formula (VI)

Z—H   (VI)

[0062] wherein Z is as previously defined, to yield the correspondingcompound of formula (Ia).

[0063] The present invention is further directed to a process for thesynthesis of compounds of the formula (Ib)

[0064] wherein

[0065] X is selected from the group consisting of NH, NR^(A) and S;

[0066] represents a 5 membered aromatic ring structure; optionallycontaining one to two additional heteroatoms selected from the groupconsisting of N, O and S;

[0067] provided that the additional heteroatoms are not at theattachment point of the —C(O)NR⁵R⁶ group;

[0068] provided that the 5 membered ring remains aromatic in nature;

[0069] wherein the 5 membered ring is optionally substituted with one tothree substituents independently selected from the group consisting ofhalogen, hydroxy, alkyl, halogenated alkyl, alkenyl, cycloalkyl, alkoxy,aryl, aralkyl, heterocyclyl, amino, mono-or di-substituted amino, cyano, nitro, —COOR, —COR, —SO₂R and —CONR^(B)R^(C); wherein the aminesubstituents are independently selected from alkyl, cycloalkyl, aryl oraralkyl; wherein the cycloalkyl, aryl or heterocyclyl may be furtheroptionally substituted with one or more substituent is independentlyselected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino,mono-or di-substituted amino, cyano or nitro;

[0070] R⁵ is selected from the group consisting of hydrogen, alkyl,aryl, aralkyl, cycloalkyl, fluorinated alkyl and heterocyclyl; whereinthe aryl, aralkyl or heterocyclyl may be optionally substituted with oneor more substituents independently selected from halogen, hydroxy,alkyl, halogenated alkyl, alkoxy, amino, mono-or di-substituted amino,cyano or nitro;

[0071] R⁶ is selected from the group consisting of hydrogen, alkyl,aralkyl, cycloalkyl, —COOR, —COR, —SO₂R, —CONR^(C)R^(D) and

[0072] where R is selected from the group consisting of alkyl, aryl,aralkyl, cycloalkyl, adamantyl, norbornyl, fluorinated alkyl andheterocycle; wherein the aryl, aralkyl or heterocycle may be optionallysubstituted with one or more substituents independently selected fromhalogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino, mono-ordi-substituted amino, cyano or nitro;

[0073] where R^(A) and R^(B) are independently selected from the groupconsisting of hydrogen, —R, —COOR, —COR, —SO₂R, —SOR and —CONR^(C)R^(D)and

[0074] where R^(C) and R^(D) are independently selected from the groupconsisting of hydrogen, alkyl, aryl, aralkyl, cycloalkyl, fluorinatedalkyl and heterocycle; wherein the aryl, aralkyl or heterocycle may beoptionally substituted with one or more substituents independentlyselected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino,mono-or di-substituted amino, cyano or nitro; or are joined together toform a 4 to 8 membered heterocyclyl ring structure;

[0075] which method comprises reacting a compound of formula (III)

[0076] with a compound of formula (IV)

[0077] wherein A is selected from F, Cl, Br and —OC(O)-t-butyl, andwherein V is a sterically hindered group, in a non-protic solvent;

[0078] and then reacting with a compound of formula (VIII)

R⁵—N═C═O   (VIII)

[0079] wherein R⁵ is as previously defined, to yield the compound offormula (Id)

[0080] reacting the compound of formula (Id) with an inorganic base toyield the compound of formula (Ie)

[0081] optionally reacting the compound of formula (le) with a compoundof formula (IX)

R⁶—Q   (IX)

[0082] wherein Q is selected from the group consisting of chlorine,bromine and iodine, in the presence of a base, to yield thecorresponding compound of formula (Ib).

[0083] A further aspect of the present invention is the synthesis ofcompounds of formula (II):

[0084] wherein

[0085] X is selected from the group consisting of NH, NR^(A) and S;

[0086] represents a 9 membered ring structure, wherein the five memberedportion of the ring structure

[0087] is aromatic and the six membered portion of the ring structure

[0088] is saturated, partially unsaturated, or aromatic;

[0089] wherein the 5 membered portion of the ring structure isoptionally substituted with one to two substituents independentlyselected from the group consisting of halogen, hydroxy, alkyl, alkenyl,halogenated alkyl, cycloalkyl, alkoxy, aryl, aralkyl, heterocyclyl,amino, mono-or di-substituted amino, cyano, nitro, —COOR, —COR, —SO₂Rand —CONR^(B)R^(C); wherein the amine substituents are independentlyselected from alkyl, cycloalkyl, aryl or aralkyl; wherein thecycloalkyl, aryl or heterocyclyl may be further optionally substitutedwith one or more substituent is independently selected from halogen,hydroxy, alkyl, halogenated alkyl, alkoxy, amino, mono-or di-substitutedamino, cyano or nitro;

[0090] wherein the 6-membered portion of the ring structure may furtheroptionally containing one to four additional heteroatoms selected fromthe group consisting of N, O and S;

[0091] wherein the 6-membered portion of the ring structure may furtherbe optionally substituted with one to four substituents independentlyselected from the group consisting of halogen, hydroxy, alkyl,halogenated alkyl, cycloalkyl, alkoxy, aryl, aralkyl, heterocyclyl,amino, mono-or di-substituted amino, cyano, nitro, —COOR, —COR, —SO₂Rand —CONR^(B)R^(C); wherein the amine substituents are independentlyselected from alkyl, cycloalkyl, aryl or aralkyl; wherein thecycloalkyl, aryl or heterocyclyl may be further optionally substitutedwith one or more substituent independently selected from halogen,hydroxy, alkyl, halogenated alkyl, alkoxy, amino, mono-or di-substitutedamino, cyano or nitro;

[0092] R² is selected from the group consisting of

[0093] Z is selected from the group consisting of hydrogen, —OR^(A),—NR^(A) R^(B),— N(R^(A))OR^(B), —SR, —CN, —N₃ and

[0094] wherein

[0095] represents a three to eight membered heterocyclyl group bound atthe N atom, wherein the heterocyclyl group is saturated, partiallyunsaturated or aromatic; when the heterocyclyl group is a saturated sixto eight membered heterocyclyl, the heterocyclyl group may optionallycontains a group selected from O, CHR, NR, S, SO, or SO₂, provided thatthat the group is separated from the N atom by at least two carbonatoms; adn wherein the heterocyclyl group is optionally substituted withone or more substituents independently selected from R;

[0096] R³ is selected from the group consisting of hydrogen, alkyl,aralkyl, cycloalkyl, fluorinated alkyl, —COR, —COOR and —CONR^(C)R^(D);wherein the aralkyl may be optionally substituted with one or moresubstituents independently selected from halogen, hydroxy, alkyl,halogenated alkyl, alkoxy, amino, mono- or di-substituted amino, cyanoor nitro;

[0097] R⁴ is selected from the group consisting of, alkyl, aryl,aralkyl, cycloalkyl, fluorinated alkyl, alkenyl, alkynyl, —COOR, —COR,—CONR^(C)R^(D), -alkyl—COOR, heterocycle and

[0098] wherein the alkyl, alkenyl, alkynyl, aryl, aralkyl or heterocyclemay be optionally substituted with one or more substituentsindependently selected from halogen, hydroxy, alkyl, halogenated alkyl,alkoxy, aryl, amino, mono-or di-substituted amino, cyano or nitro;wherein Y is selected from the group consisting of O, S and NR^(A);

[0099] R⁵ is selected from the group consisting of hydrogen, alkyl,aryl, aralkyl, cycloalkyl, fluorinated alkyl and heterocycle; whereinthe aryl, aralkyl or heterocycle may be optionally substituted with oneor more substituents independently selected from halogen, hydroxy,alkyl, halogenated alkyl, alkoxy, amino, mono-or di-substituted amino,cyano or nitro;

[0100] R⁶ is selected from the group consisting of hydrogen, alkyl,aralkyl, cycloalkyl, —COOR, —COR, —SO₂R, —CONR^(C)R^(D) and

[0101] where R is selected from the group consisting of alkyl, aryl,aralkyl, cycloalkyl, adamantyl, norbornyl, fluorinated alkyl andheterocycle; wherein the aryl, aralkyl or heterocycle may be optionallysubstituted with one or more substituents independently selected fromhalogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino, mono-ordi-substituted amino, cyano or nitro;

[0102] where R^(A) and R^(B) are independently selected from the groupconsisting of hydrogen, —R, —COOR, —COR, —SO₂R, —SOR and —CONR^(C)^(B)R^(D) and

[0103] where R^(C) and R^(D) are independently selected from the groupconsisting of hydrogen, alkyl, aryl, aralkyl, cycloalkyl, fluorinatedalkyl and heterocycle; wherein the aryl, aralkyl or heterocycle may beoptionally substituted with one or more substituents independentlyselected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino,mono-or di-substituted amino, cyano or nitro; or are joined together toform a 4 to 8 membered heterocyclyl ring structure;

[0104] according to either of the processes disclosed herein, withappropriate substitution of a compound of formula (VII)

[0105] for the corresponding monocyclic compound of formula (III)

DETAILED DESCRIPTION OF THE INVENTION

[0106] As used herein, the term “alkyl” whether used alone or as part ofa substituent group, shall denote straight and branched chains. Forexample, alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, t-butyl, pentyl and the like. Unless otherwisenoted, “lower” when used with alkyl means a carbon chain composition of1 to 4 carbon atoms. Similarly, as used herein, the term “alkenyl”,whether used alone or as part of a substituent group, shall denotestraight and branched chain alkene radicals, i.e. straight or branchedchains containing at least one double bond. For example, alkenylradicals include allyl, vinyl, and the like. Similarly, as used herein,the term “alkynyl”, whether used alone or as part of a substituentgroup, shall denote straight and branched chain alkyne radicals, i.e.,straight or branched chains containing at least one triple bond. Forexample, alkynyl radicals include -CCH, —CH₂CCH (propargyl), —CH₂CCCH₃,and the like.

[0107] As used herein, unless otherwise noted, “alkoxy” shall denote anoxygen ether radical of the above described straight or branched chainalkyl groups. For example, methoxy, ethoxy, n-propoxy, sec-butoxy,t-butoxy, n-hexyloxy and the like.

[0108] As used herein, “halogen” shall mean chlorine, bromine, fluorineand iodine.

[0109] As used herein, unless otherwise noted, “aryl” shall refer tocarbocyclic aromatic groups such as phenyl, naphthyl, and the like.

[0110] As used herein, unless otherwise noted, “aralkyl” shall mean anylower alkyl group substituted with an aryl group such as phenyl,naphthyl and the like. Suitable examples of aralkyls include benzyl,1-(phenyl)ethyl, naphthylmethyl, and the like.

[0111] As used herein, the term “cycloalkyl” shall denote any monocyclicthree to eight membered, saturated carbocyclic ring structure. Suitableexamples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cycloocytyl.

[0112] As used herein, unless otherwise noted, the terms “heterocycle”,“heterocyclyl” and “heterocyclo” shall denote any five or six memberedmonocyclic, nine or ten membered bicyclic or thirteen or fourteenmembered tricyclic ring structure containing at least one heteroatomselected from the group consisting of N, O and S, optionally containingone to four additional heteroatoms, wherein the ring structure issaturated, partially unsaturated, aromatic or partially aromatic. Theheterocyclyl group may be attached at any heteroatom or carbon atomwhich results in the creation of a stable structure.

[0113] Exemplary monocyclic heterocyclic groups can includepyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl,imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl,isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl,isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl,oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl,4-piperidonyl, pyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, tetrahydropryanyl, tetrahydrothiopyranyl,tetrahydrothiopyranyl sulfone, morpholinyl, thiomorpholinyl,thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dixolane andtetrahydro-1,1-dioxothienyl, dioxanyl, isothiazolidinyl, triazinyl,triazolyl and the like.

[0114] Exemplary bicyclic heterocyclic groups include benzothiazolyl,benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl,quinolinyl—N-oxide, tetrahydroisoquinolinyl, isoquinolinyl,benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl,coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopridyl,furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,1-b]pyridinyl), orfuro[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as3,4-dihydro-4-oxo-quinazolinyl), benzisothiazolyl, benzisoxazolyl,benzodiazinyl, benzofurazanyl, benzothiopyranyl, benzotriazolyl,benzpyrazolyl, dihydrobenzofuryl, dihydrobenzothienyl,dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone,dihydrobenzopyranyl, indolinyl, isochromanyl, isoindolinyl,naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl,quinazolinyl, tetrahydroquinolinyl, thienofuryl, thienopyridyl,thienothienyl and the like.

[0115] Exemplary tricyclic heterocylclic groups include phenoxazinyl,phenazinyl, phenothiazinyl, carbozolyl, perminidinyl, phenanthrolinyl,carbolinyl, naphthothienyl, thianthrenyl, and the like.

[0116] In the definition of Z, suitable examples of the

[0117] group include pyrazol-1-yI, imidazol-1-yl, pyrrol-1-yl,1,2,4-triazol-1-yl, 1,2,4-triazol-4-yl, 1,2,3-triazol-1-yl,aziridin-1-yl, pyrrolidin-1-yl, piperidin-1yl, piperazin-1-yl,morpholin-1-yl, 4-methyl-diazepin-1-yl, azepin-1-yl, diazepin-1-yl,4-methyl-piperazin-1-yl, and the like.

[0118] When a particular group is “substituted” (e.g., cycloalkyl, aryl,heterocyclyl, heteroaryl), that group may have one or more substituents,preferably from one to five substituents, more preferably from one tothree substituents, most preferably from one to two substituents,independently selected from the list of substituents.

[0119] With reference to substituents, the term “independently” meansthat when more than one of such substituents is possible, suchsubstituents may be the same or different from each other.

[0120] Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.Thus, for example, a “phenylalkylaminocarbonylalkyl” substituent refersto a group of the formula

[0121] The term “subject” as used herein, refers to an animal,preferably a mammal, most preferably a human, who has been the object oftreatment, observation or experiment.

[0122] The term “therapeutically effective amount” as used herein, meansthat amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease or disorder being treated.

[0123] As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

[0124] For the purposes of this invention, the term “chemical library”means a collection of molecules prepared by the method of the inventionbased on logical design by means of simultaneous or parallel chemicalreactions. Each species of molecule in the library is referred to as amember of the library.

[0125] Abbreviations used in the specification, particularly the Schemesand Examples, are as follows: DIPEA = Diisopropylethylamine DMF =N,N-Dimethylformamide Et = Ethyl (-CH₂CH₃) Ex # = Example Number Me =Methyl (-CH₃) Pd(PPh₃)₄ = Palladium, tetrakis(triphenylphosphine)- Ph =Phenyl (-C₆H₅) TEA = Triethylamine TFA = Trifluoroacetic acid THE =Tetrahydrofuran

[0126] Compounds of formula (Ia), compounds of formula (I) wherein R² is

[0127] may be prepared using solution phase chemistry according to theprocess outlined in Scheme 1.

[0128] Accordingly, a compound of formula (l1l), a known compound orcompound prepared by known methods, is reacted sequentially with acompound of formula (IV), wherein A is selected from F, Cl, Br or—OC(O)-t-butyl and wherein V is a sterically hindered group such ast-butyl, adamantyl, N(alkyl)₂, N(aryl)₂, 2,6-dimethylphenyl,2,6-disubstituted phenyl, O-t-butyl, O-isopropyl, O-adamantyl, and thelike, at a temperature in the range of about 0° C. to about reflux in anon-protic solvent such as acetonitrile, dioxane, THF, and the like;

[0129] and then reacted with a compound of formula (V), wherein W is —O,—NSO₂R, —NSOR, —NCOR, —NCOOR, —NCONR^(C)R^(D), —NOCOR or —NR, in thepresence of an organic base such as TEA, DIPEA, and the like, to yieldthe corresponding compound of formula (Ic).

[0130] Compounds of formula (Ic) wherein W is O may be further convertedto compounds of formula (Ia), wherein Z is not hydrogen, according tothe process outlined in Scheme 2.

[0131] Accordingly, the compound of formula (Ic) is reacted with acompound of formula (VI), in a non-protic solvent such as acetonitrile,dioxane, THF, and the like, in the presence of an acid such as TFA, andthe like, at a temperature in the range of about 0° C. to about reflux,preferably at about reflux temperature, to form the correspondingcompound of formula (Ia).

[0132] When in the compound of formula (Ia) Z is H, the compound offormula (Ic) is reduced by hydrogenation with a metal catalyst such aspalladium, platinum, palladium on carbon, and the like, in an organicsolvent such as methanol, ethanol, ethyl acetate, acetic acid, THF, DMF,and the like, to form the corresponding compound of formula (Ia).

[0133] Similarly, compounds of formula (II) wherein R² is

[0134] may be prepared according to the process as outlined in Schemes1&2, with appropriate substitution of a compound of formula (VII)

[0135] for the compound of formula (III), to yield the correspondingcompound of formula (IIa)

[0136] Compounds of formula (I) wherein R² is

[0137] may be prepared according to the process outlined in Scheme 3.

[0138] More specifically, a compound of formula (III), a known compoundor compound prepared by known methods, is reacted sequentially with acompound of formula (IV), wherein A is selected from F, Cl, Br or—OC(O)-t-butyl, and wherein V is a sterically hindered group such ast-butyl, adamantyl, N(alkyl)₂, N(aryl)₂, 2,6-dimethylphenyl,2,6-disubstituted phenyl, O-t-butyl, O-isopropyl, O-adamantyl, and thelike, at a temperature in the range of about 0° C. to about reflux,preferably a about reflux temperature, in a non-protic solvent such asacetonitrile, dioxane, THF, and the like;

[0139] and then reacted with a suitably substituted isocyanate offormula (VIII), in the presence of a base such as TEA, DIPEA, and thelike, at a temperature in the range of about 0° C. to about reflux,preferably at about reflux temperature, to form the correspondingcompound of formula (Id).

[0140] The compound of formula (Id) is further optionally reacted withan inorganic base such as sodium hydroxide, to form the correspondingcompound of formula (Ie). Alternatively, the compound of formula (Id) isfurther optionally reacted with an inorganic base such as potassiumcarbonate, sodium carbonate, and the like, in the presence of water, toform the corresponding compound of formula (Ie).

[0141] The compound of formula (Ie) is optionally further reacted toform the compound of formula (1b) according to the process outlined inScheme 4.

[0142] Accordingly, the compound of formula (Ie) is reacted with acompound of formula (IX), wherein Q is selected from the groupconsisting of chlorine, bromine and iodine, in the presence of a basesuch as NaH, potassium t-butoxide, potassium carbonate, and the like, toyield the corresponding compound of formula (Ib).

[0143] Similarly, compounds of formula (II) wherein R² is

[0144] may be prepared using the solution phase chemistry outlined inScheme 5, with appropriate substitution of a compound of formula (VII)

[0145] for the compound of formula (III), to produce the correspondingcompound of formula (IIb).

[0146] The following Examples are set forth to aid in the understandingof the invention, and are not intended and should not be construed tolimit in any way the invention set forth in the claims which followthereafter.

EXAMPLE 1

[0147]

[0148] To a suspension of 1-benzylimidazole (315 mg, 2.0 mmol) inacetonitrile (3 mL) at 0° C. and under nitrogen was added rapidlydropwise a solution of diisopropylcarbamyl chloride (396 mg, 2.4 mmol)in acetonitrile (5 mL). To the slightly cloudy solution was addedbenzaldehyde (0.31 mL, 3.0 mmol), followed by N,N-diisopropylethylamine(1.1 mL, 6.3 mmol). The ice bath was removed and after stirring for 10min, the cloudy yellow solution was refluxed for 24 h, cooled to roomtemperature, and concentrated in vacuo. The residue was dissolved inethyl acetate and washed successively with 2N NaOH, water, and saturatedbrine. The organic layer was dried over magnesium sulfate, filtered, andconcentrated to yield a pale yellow oil (1.01 g). Flash chromatographyon silica (50 mm×7 in) eluted with ethyl acetate-hexanes (1:1) yieldedthe product as white crystals.

[0149] Yield: 611 mg, 78%

[0150] mp 106-109° C.;

[0151] MS (ESP) m/z 392 (MH⁺)

EXAMPLE 2

[0152]

[0153] To a solution of 1-methylimidazole (1.64 g, 20 mmol) anddiisopropylcarbamyl chloride (3.6 g, 22 mmol) in acetonitrile (30 mL) atroom temperature and under nitrogen was added dropwise benzaldehyde (3.1mL, 30 mmol), followed by N,N-diisopropylethylamine (10 mL, 60 mmol).The resulting mixture was stirred at room temperature for 24, and thenconcentrated in vacuo. The residue was purified by flash chromatographyon silica (BIOTAGE, FLASH 40i, Charlottesville, Va., USA) eluted withethyl acetate-hexanes (1:1) to yield the title product as whitecrystals.

[0154] Yield: 6 g, 95%

[0155] mp 67-68° C.;

[0156] MS (ESP) m/z 317 MH⁺)

EXAMPLES 3-29

[0157] Selected compounds listed in Table 1 were similarly preparedfollowing rocedure outlined in Example 1 and Example 2, with appropriateselection substitution of reagents, as listed in Table 2. TABLE 1

Ex # R¹⁰ R¹¹ R¹² Z R³ R⁴  3 H H benzyl OC(O)N(i-propyl)₂ H t-butyl  4 HH benzyl OC(O)N(i-propyl)₂ H i-propyl  5 H H benzyl OC(O)N(i-propyl)₂ Hcyclohexyl  6 H H benzyl OC(O)N(i-propyl)₂ H phenylethyl  7 H H benzylOC(O)N(i-propyl)₂ H benzyl  8 H H benzyl OC(O)N(i-propyl)₂ H4-methoxyphenyl  9 H H benzyl OC(O)N(i-propyl)₂ H 4-methoxyphenyl 10 H Hbenzyl OC(O)N(i-propyl)₂ H 4-chlorophenyl 11 H H benzylOC(O)N(i-propyl)₂ CF₃ phenyl 12 H H benzyl OC(O)N(i-propyl)₂—C(O)O—CH₂CH₃

13 H H benzyl OC(O)N(i-propyl)₂ H —CH═CH₂ 14 H H benzylOC(O)N(i-propyl)₂ H

15 H H benzyl OC(O)N(i-propyl)₂ H

16 H H benzyl N(phenyl)-C(O)- H phenyl N(i-propyl)₂ 17 H H benzylN(SO₂phenyl)- H phenyl C(O)-N(i-propyl)₂ 18 H H methyl—OC(O)N(i-propyl)₂ H phenyl 19 H Cl methyl —OC(O)N(i-propyl)₂ H phenyl20 H H Phenyl —OC(O)N(i-propyl)₂ H phenyl 21 Cl Cl methyl—OC(O)N(i-propyl)₂ H phenyl 22 H H methyl —OC(O)N(ethyl)₂ H phenyl 23 HH methyl —OC(O)N(methyl)₂ H phenyl 24 H H methyl —OC(O)N(i-propyl)₂ Hethyl 25 H H methyl —OC(O)N(i-propyl)₂ H —CH═CHCH₃ 26 H H methyl—OC(O)N(methyl)₂ H 2-pyridinyl 27 H H methyl —OC(O)N(methyl)₂ H-C(O)-phenyl 28 H H methyl —OC(O)N(methyl)₂ -C(O)O- phenylethyl CH₂CH₃29 H C(O)OCH₃ methyl —OC(O)N(methyl)₂ H phenyl

[0158] TABLE 2 Preparation Conditions Reaction Reflux Time Ex # Temp (°C.) (h) Yield (%) mp (° C.) mass spec (MH⁺) 3 reflux 24 66 48-52 372 4room temp 66 85 oil 358 5 room temp 24 56 oil 398 6 room temp 29 7573-78 420 7 reflux 20 32 oil 406 8 reflux 21 30 oil 277 M⁺ w/loss ofOC(O)(i-propyl)₂ 9 room temp 67 73 oil 277 M⁺ w/loss of OC(O)(i-propyl)₂10 room temp 30 77 113-115 426 11 room temp 72 89 124-126 460 12 roomtemp 68 73 oil 488 13 room temp 68 67 oil 342 14 room temp 72 76 oil 51515 room temp 144 79 oil 416 16 reflux 21 12 oil 467 17 room temp 72 88132-139 531 18 room temp 24 90 67-68 316 19 50 24 66 oil 350 20 roomtemp 24 86 104-105 378 21 reflux 20 42   118-118.5 384 22 60 20 91 oil288 23 60 20 93 102-102 260 24 room temp 48 96 oil 268 25 room temp 4865 oil 280 26 room temp 20 78 oil 261 27 room temp 20 70 92-93 288 28room temp 20 60 112-113 360 29 room temp 48 80 134-135 318

EXAMPLES 30-32

[0159] Selected compounds listed in Table 3 were similarly preparedfollowing the procedure outlined in Example 1, with appropriateselection and substitution of reagents, as listed in Table 4. Note thatthe conditions as disclosed in Example 31 yielded a mixture of compoundsare defined below. TABLE 3

Ex # Z R³ R⁴ 30 —OC(O)O(t-butyl) H phenyl 31 —OC(O)O(t-butyl) H phenyl—OC(O)(phenyl) H phenyl 32 —OC(O)(t-butyl) H phenyl

[0160] TABLE 4 Preparation Conditions Reaction T Reflux mass spec Ex #(° C.) Time (h) Yield (%) mp (° C.) (MH⁺) 30 room temp 23 44 77-79 36531 reflux 21 52 75-79 365 11 oil 369 32 reflux 21 32 oil 349

[0161]

EXAMPLE 33

[0162] To a solution of 1-methylimidazole (164 mg, 2.0 mmol) inanhydrous acetonitrile (5 mL) at room temperature and under nitrogen wasadded dropwise benzaldehyde (0.31 mL, 3.0 mmol) and a solution ofdi-teff-butyl dicarbonate (480 mg, 2.2 mmol) in anhydrous acetonitrile(1 mL). The mixture was stirred at room temperature for 3 hours, thenconcentrated in vacuo. The residue was purified by flash chromatographyon silica eluted with ethyl acetate-hexanes (2:3) to yield the titleproduct as white crystals.

[0163] Yield: 421 mg, 77%

[0164] mp 95-96° C.;

[0165] MS (ESP) m/z 289 MH⁺)

EXAMPLE 34

[0166]

[0167] To a solution of 1-benzylimidazole (313 mg, 2.0 mmol) inanhydrous acetonitrile (2 mL) at room temperature and under nitrogen wasadded dropwise a solution of adamantylfluoroformate (498 mg, 2.5 mmol)in anhydrous acetonitrile (2 mL), a solution of benzyliminoacetic acidethyl ester (573 mg, 3.0 mmol) in anhydrous acetonitrile (2 mL), anddiisopropylethyl amine (1.1. mL, 6.3 mmol). The mixture was stirred atroom temperature for 16 hours, then concentrated in vacuo. The residuewas purified by flash chromatography on silica eluted with ethylacetate-hexanes (1:3) to yield the title product as white crystals.

[0168] Yield: 441 mg, 42%

[0169] mp 83-85° C.;

[0170] MS (ESP) m/z 538 MH⁺)

EXAMPLES 35-40

[0171] Selected compounds listed in Table 5 were similarly preparedfollowing the procedure outlined in Example 1, Example 2 and Example 33with appropriate selection and substitution of reagents, as listed inTable 6. TABLE 5

Ex # Z R³ R⁴ 35 —N(C(O)N(i-propyl)₂)OC(O)CH₃ H phenyl 36—N(benzyl)C(O)N(i-propyl)₂ H phenyl 37 —N(benzyl)C(O)N(i-propyl)₂ Hphenyl 38 —N(SO₂phenyl)C(O)O-t-butyl H phenyl 39—N(SO₂-p-toluenyl)C(O)O-t-butyl methyl phenyl 40 —N(benzyl)C(O)O-t-butylH —C(O)O-ethyl

[0172] TABLE 6 Reaction T Reaction Yield mp mass spec Ex # (° C.) Time(h) (%) (° C.) (MH⁺) 35 room temp 16 60 oil 248 M⁺ w/loss ofC(O)N(i-propyl)₂ 36 room temp 15 65 oil 248 M⁺ w/loss ofC(O)N(i-propyl)₂ 37 room temp 15 45 oil 248 M⁺ w/loss ofC(O)N(i-propyl)₂ 38 room temp 3 60 51-52 503 39 room temp 3 35 56-57 53140 room temp 3 55 oil 449

EXAMPLES 41-50

[0173] Selected compounds listed in Table 7 and Table 8were similarlyprepared following the procedure outlined in Example 1, Example 2 andExample 33, with appropriate selection and substitution of reagents, aslisted in Table 9 TABLE 7

Ex # Z R R 41 OC(O)N(i-propyl)₂ H phenyl

Ex # Z R¹⁰ R¹¹ R³ R⁴ 42 OC(O)N(i-propyl)₂ H H H phenyl 43—OC(O)N(i-propyl)₂ H H H phenyl 44 —OC(O)N(i-propyl)₂ H H Hp-nitrophenyl 45 —OC(O)N(i-propyl)₂ H H CF₃ phenyl 46 —OC(O)N(i-propyl)₂CH₃ CH═CH₂ H phenyl 47 —OC(O)N(i-propyl)₂ CH₃ CH₃ H phenyl 48—OC(O)O-t-butyl H H H phenyl 49 —OC(O)NMe2 H H H phenyl

[0174] TABLE 8

Ex # Z R³ R⁴ 50 —OC(O)N(methyl)₂ H phenyl

[0175] TABLE 9 Preparation Conditions Reaction T Reflux Yield Ex # (°C.) Time (h) (%) mp (° C.) mass spec (MH⁺) 41 reflux 23 88 126-128 36642 reflux 22 39 70-71 319 43 reflux 52 17 65-68 319 44 room temp 48 42oil 364 45 room temp 48 55 82-82 387 46 reflux 24 42 oil 359 47 reflux24 46 98-99 347 48 60 20 65 oil 292 49 60 20 61 45-47 263 50 60 20 41oil 313

EXAMPLES 51-52

[0176] Selected compounds listed in Table 10 were similarly preparedfollowing the procedure outlined in Example 2, with appropriateselection and substitution of reagents, as listed in Table 11. TABLE 10

Ex # Z R³ R⁴ 51 —OC(O)N(i-propyl)₂ H phenyl 52 —OC(O)N(i-propyl)₂ Hphenyl

EXAMPLE 53

[0177] TABLE 11 Preparation Conditions Reaction T Time Yield mp Ex # (°C.) (h) (%) (° C.) mass spec (MH⁺) 51 room temp 23 68 115-116 393 52room temp 22 66 93-94 393

[0178]

[0179] To a suspension of 1-benzylimidazole (317 mg, 2.0 mmol) inacetonitrile (3 mL) at room temperature was added rapidly dropwise asolution of diisopropylcarbamyl chloride (396 mg, 2.4 mmol) inacetonitrile (5 mL). To the slightly cloudy solution was addedphenylacetaldehyde (0.35 mL, 3.0 mmol), followed byN,N-diisopropylethylamine (1.1 mL, 6.3 mmol). The mixture was refluxedfor 5.5h and cooled to room temperature. To the resulting mixture wasthen added a solution of diisopropylcarbamyl chloride (396 mg, 2.4 mmol)in acetonitrile (5 mL), followed by phenylacetaldehyde (0.35 mL, 3.0mmol) and N,N-diisopropylethylamine (1.1 mL, 6.3 mmol). The reactionmixture was refluxed for 24h, cooled to room temperature, and thencharged again with a solution of diisopropylcarbamyl chloride (396 mg,2.4 mmol) in acetonitrile (5 mL), followed by phenylacetaldehyde (0.35mL, 3.0 mmol) and N,N-diisopropylethylamine (1.1 mL, 6.3 mmol). Themixture was refluxed for an additional 21 h, cooled to room temperature,and concentrated in vacuo. The residue was dissolved in ethyl acetateand washed successively with 2N NaOH, water, and saturated brine. Theorganic layer was dried over magnesium sulfate, filtered, andconcentrated to a yellow oil (2.70 g). Flash chromatography on silica(50 mm×8 in) eluted with 40% ethyl acetate in hexanes yielded theproductas pale yellow crystals.

[0180] Yield: 632 mg, 78%

[0181] mp 75-79° C.;

[0182] MS (ESP) m/z 406 MH⁺)

EXAMPLE 54

[0183]

[0184] To a suspension of 1-benzylimidazole (317 mg, 2.0 mmol) inacetonitrile (3 mL) at room temperature and under nitrogen was addedrapidly dropwise a solution of duisopropylcarbamyl chloride (391 mg, 2.4mmol) in acetonitrile (5 mL). To the slightly cloudy solution was addedphenylisocyanate(0.33 mL, 3.0 mmol), followed byN,N-diisopropylethylamine (1.1 mL, 6.3 mmol). The mixture was refluxedfor 21 h, cooled to room temperature, and concentrated in vacuo. Theresidue was dissolved in ethyl acetate and washed successively with 2NNaOH, water, and saturated brine. The organic layer was dried overmagnesium sulfate, filtered, and concentrated to yield a yellow oil(1.22 g). Flash chromatography on silica (50 mm×6 in) eluted with 25%ethyl acetate in hexanes yielded a crystalline solid product (1.0 g)containing an impurity. Flash chromatography of this material on silica(50 mm×6 in) eluted with 20% acetone in hexanes yielded a pale yellowfoam (825 mg). The foam was recrystallized from ethyl acetate/hexanes toyield the title product as white crystals.

[0185] Yield: 577 mg, 71%

[0186] mp 125.5-127° C.;

[0187] MS (ESP) m/z 405 MH⁺)

EXAMPLE 55

[0188]

[0189] To a suspension of imidazole (140 mg, 2.0 mmol) in acetonitrile(3 mL) at room temperature and under nitrogen was added rapidly dropwisea solution of dusopropylcarbamyl chloride (786 mg, 4.8 mmol) inacetonitrile (5 mL). To the mixture was added benzaldehyde (0.31 mL,(3.0 mmol), followed by N,N-duisopropylethylamine (1.5 mL, 8.6 mmol).The reaction mixture was refluxed for 22h, cooled to room temperature,and concentrated in vacuo. The residue was dissolved in ethyl acetateand washed successively with dilute brine (2X) and saturated brine. Theorganic layer was dried over magnesium sulfate, filtered, andconcentrated to ayellow solid (1.19 g). Flash chromatography on silica(50 mm×6 in) eluted with 45% ethyl acetate in hexanes yielded theproduct as white crystals.

[0190] Yield: 536 mg, 61%

[0191] mp 173-175° C.;

[0192] MS (ESP) m/z 429 MH⁺)

EXAMPLE 56

[0193]

[0194] A solution of the product prepared in Example 1 (392 mg 1.0 mmol)in tetrahydrofuran (5 mL), water (1 mL), and trifluoroacetic acid (0.5mL) was refluxed for 11 h. After cooling, the reaction mixture wasdiluted with 1:1 ethyl acetate/ethyl ether and washed successively with2N NaOH, water, and saturated brine. The organic layer was dried overmagnesium sulfate, filtered, and concentrated to yield a white solid.Flash chromatography on silica (25 mm×7 in) eluted with 5% methanol inmethylene chloride yielded the product as white crystals.

[0195] Yield: 222 mg, 84%

[0196] mp 111-114° C.;

[0197] MS (ESP) m/z 265 MH⁺)

EXAMPLE 57

[0198]

[0199] A solution of the product prepared in Example 1 (391 mg, 1.0mmol) in anhydrous methanol (5 mL) and trifluoroacetic acid (0.5 mL)under a nitrogen atmosphere was refluxed for 28h. After cooling,trifluoroacetic acid (0.5 mL) was added and the refluxing continued for24h. After cooling, the reaction mixture was diluted with 1:1 ethylacetate/ethyl ether and washed successively with 2N NaOH, water, andsaturated brine. The organic layer was dried over magnesium sulfate,filtered, and concentrated to yield a white film. Flash chromatographyon silica (25 mm×7 in) eluted with 80% ethyl acetate in hexanes yieldedthe product as pale yellow crystals.

[0200] Yield: 167 mg, 60%

[0201] mp 68-71.5° C.;

[0202] MS (ESP) m/z 279 MH⁺)

EXAMPLE 58

[0203]

[0204] A solution of the product prepared in Example 1 (781 mg, 2.0mmol) in anhydrous ethanol (10 mL) and trifluoroacetic acid (0.5 mL)under a nitrogen atmosphere was refluxed for 8h. After cooling, thereaction mixture was concentrated, diluted with ethyl acetate and thenwashed successively with 2N NaOH, water, and saturated brine. Theorganic layer was dried over magnesium sulfate, filtered, andconcentrated to yield a yellow oil (0.77 g). Flash chromatography onsilica (50 mm×6 in) eluted with 60% ethyl acetate in hexanes yielded theproduct as a colorless oil.

[0205] Yield: 492 mg, 84%

[0206] MS (ESP) m/z 293 MH⁺)

EXAMPLE 59

[0207]

[0208] A solution of the product prepared in Example 1 (787 mg, 2.0mmol) and acetamide (1.18 g, 20 mmol) in tetrahydrofuran (10 mL) andtrifluoroacetic acid (0.5 mL) under a nitrogen atmosphere was refluxedfor 18h. After cooling, the reaction mixture was diluted with 1:1 ethylacetate/ethyl ether and washed successively with 2N NaOH, water, andsaturated brine. The organic layer was dried over magnesium sulfate,filtered, and concentrated to yield a white solid (555 mg). The solidwas recrystallized from ethyl acetate/hexanes to yield the title productas white crystals.

[0209] Yield: 385 mg, 63%

[0210] mp 171-176° C.;

[0211] MS (ESP) m/z 306 MH⁺)

EXAMPLE 60

[0212]

[0213] A solution of the product prepared in Example 1 (784 mg, 2.0mmol) and methanesulfonamide (1.90 g, 20 mmol) in tetrahydrofuran (10mL) and trifluoroacetic acid (0.5 mL) under a nitrogen atmosphere wasrefluxed for 24h. After cooling, the reaction mixture was concentrated,diluted with 1:1 ethyl acetate/ethyl ether and then washed successivelywith 1 N sodium carbonate, water, and saturated brine. The organic layerwas dried over magnesium sulfate, filtered, and concentrated to yield awhite film (0.75 g). Flash chromatography on silica (50 mm×6 in) elutedwith 4% methanol in methylene chloride yielded the product as whitecrystals.

[0214] Yield: 514 mg, 75%

[0215] mp 162-163° C.;

[0216] MS (ESP) m/z 342 MH⁺)

EXAMPLE 61

[0217]

[0218] A solution of the product prepared in Example 40 (364 mg, 1.0mmol) in tetrahydrofuran (5 mL), water (1 mL) and trifluoroacetic acid(0.5 mL) was refluxed for 18h. After cooling, the reaction mixture wasdiluted with ethyl acetate and washed successively with 1 N sodiumcarbonate, water, and saturated brine. The organic layer was dried overmagnesium sulfate, filtered, and concentrated to yield white crystals.Flash chromatography on silica (25 mm×8 in) eluted with 3% methanol inmethylene chloride yielded the product as white crystals.

[0219] Yield: 148 mg, 62%

[0220] mp 160.5-162° C.;

[0221] MS (ESP) m/z 239 MH⁺)

EXAMPLE 62

[0222]

[0223] To a solution of the product prepared in Example 2 (158 mg, 0.5mmol) in anhydrous THF (5 mL) and trifluoroacetic acid (0.22 mL, 3 mmol)under a nitrogen atmosphere was added aniline (0.47 mL, 5 mmol). Theresulting mixture was refluxed for 4 h. After cooling, the reactionmixture was diluted with dichloromethane and washed successively with 2NNaOH, water, and saturated brine. The organic layer was dried overmagnesium sulfate, filtered, and concentrated to yield a yellow oil.Flash chromatography on silica (20 mm×6 in) eluted with 50% ethylacetate in hexanes yielded the product as light yellow crystals.

[0224] Yield: 102 mg, 81%

[0225] mp 110-112° C.;

[0226] MS (ESP) m/z 264 (MH⁺)

EXAMPLE 63

[0227]

[0228] To a solution of the product prepared in Example 2 (158 mg, 0.5mmol) in anhydrous THF (5 mL) and trifluoroacetic acid (0.33 mL, 4.5mmol) under a nitrogen atmosphere was added piperidine (0.5 mL, 5 mmol)and BF₃*Et₂O (0.1 mL, 0.75 mmol) successively. The resulting mixture wasrefluxed for 4. After cooling, the reaction mixture was diluted withdichloromethane and washed successively with 2N NaOH, water, andsaturated brine. The organic layer was dried over magnesium sulfate,filtered, and concentrated to yield a yellow oil. Flash chromatographyon silica (20 mm×6 in) eluted with 5% methanol in ethyl acetate yieldedthe product as a light yellow oil.

[0229] Yield: 109 mg, 85%

[0230] MS (ESP) m/z 256 MH⁺)

EXAMPLE 64

[0231]

[0232] To a suspension of the product prepared in Example 2 (158 mg, 0.5mmol) and H₂NOMeoHCI (555 mg, 5 mmol) in anhydrous THP (5 mL) under anitrogen atmosphere was added BF₃Et₂O (0.2 mL, 1.5 mmol). The resultingmixture was refluxed for 4. After cooling, the reaction mixture wasfiltered. The filtrate was dissolved in 10% methanol in dichloromethane,and washed successively with saturated NaHCO₃, water, and saturatedbrine. The organic layer was dried over magnesium sulfate, filtered, andconcentrated to yield a yellow oil. Flash chromatography on silica (20mm×6 in) eluted with 10% methanol in dichloromethane yielded the productas white crystals.

[0233] Yield: 80 mg, 73%

[0234] mp 119-122° C.;

[0235] MS (ESP) m/z 218 MH⁺)

EXAMPLE 65

[0236]

[0237] To a solution of the product prepared in Example 2 (158 mg, 0.5mmol) in anhydrous DMF (5 mL) under a nitrogen atmosphere was added NaN₃(98 mg, 1.5 mmol) and pyridinium p-toluenesufonate (catalytic amount).The resulting mixture was stirred at 70° C. overnight. After cooling,the reaction mixture was diluted with dichloromethane and washedsuccessively with saturated NaHCO₃, water, and saturated brine. Theorganic layer was dried over magnesium sulfate, filtered, andconcentrated to yield a yellow oil. Flash chromatography on silica (20mm×6 in) eluted with 2% methanol in ethyl acetate yielded the product asa oil.

[0238] Yield: 85 mg, 80%

[0239] MS (ESP) m/z 214 MH⁺)

EXAMPLES 66-79

[0240] Selected compounds listed in Table 12 were similarly preparedfollowing the procedure outlined in Example 62 to 65, with appropriateselection and substitution of reagents, as listed in Table 13. TABLE 12

Ex # Z R¹² R³ R⁴ 66 morpholin-1-yl CH₃ H phenyl 67 —S-phenyl CH₃ Hphenyl 68 —NH-pyridin-2-yl CH₃ H phenyl 69 —NH(CH₂OH₂OH) CH₃ H phenyl 70—S—CH₂CH₂NH₂ CH₃ H phenyl 71 —NH-benzyl CH₃ H phenyl 72 4-methylpiperazin-1-yl CH₃ H phenyl 73 imidazol-1-yl CH₃ H phenyl 74 —NH-phenylCH₃ H ethyl 75 —NH-phenyl CH₃ H —CH═CH₂CH₃ 76 piperidin-1-yl CH₃ H—CH═CH₂CH₃ 77 morpholin-1-yl CH₃ H —CH═CH₂CH₃ 78 morpholin-1-yl CH₃ Hethyl

Ex # Z R³ R⁴ 79 piperidin-1-yl H phenyl

[0241] TABLE 10 PREPARATION CONDITIONS reaction T reflux time yield mpmass spec Ex # (° C.) (h) (%) (° C.) (MH⁺) 66 reflux 15 82 oil 258 67reflux 6 86 oil 281 68 reflux 3 85 oil 265 69 reflux 20 65 oil 232 70reflux 20 70 oil 249 71 reflux 24 76 oil 278 72 reflux 20 81 oil 271 73reflux 20 75 oil 234 74 reflux 72 74 oil 216 75 reflux 4 88 122-123 22876 reflux 4 60 oil 220 77 reflux 4 68 oil 222 78 reflux 72 40 oil 210 79reflux 20 50 oil 259

[0242] While some the previous examples describe the purification ofreaction products by flash chromatography, these reaction products canalso be purified in a high-throughput mode using high-throughputreverse-phase or high-throughput normal phase HPLC instruments, thereby,increasing the efficiency of compounds library syntheses.

[0243] While the foregoing specification teaches the principles of thepresent invention, with examples provided for the purpose ofillustration, it will be understood that the practice of the inventionencompasses all of the usual variations, adaptations and/ormodifications as come within the scope of the following claims and theirequivalents.

We claim:
 1. A method of synthesizing highly substituted azole compoundshaving the general formula (Ia):

wherein X is selected from the group consisting of NH, NR^(A) and S;

represents a 5 membered aromatic ring structure; optionally containingone to two additional heteroatoms selected from the group consisting ofN, O and S; provided that the additional heteroatoms are not at theattachment point of the

R⁴ group; provided that the 5 membered ring remains aromatic in nature;wherein the 5 membered ring is optionally substituted with one to threesubstituents independently selected from the group consisting ofhalogen, hydroxy, alkyl, halogenated alkyl, alkenyl, cycloalkyl, alkoxy,aryl, aralkyl, heterocyclyl, amino, mono-or di-substituted amino, cyanonitro, —COOR, —COR, —SO₂R and —CONR^(B)R^(C); wherein the aminesubstituents are independently selected from alkyl, cycloalkyl, aryl oraralkyl; wherein the cycloalkyl, aryl or heterocyclyl may be furtheroptionally substituted with one or more substituent is independentlyselected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino,mono-or di-substituted amino, cyano or nitro; Z is selected from thegroup consisting of —OR^(A), —NR^(A) R^(B), —N(R^(A))OR^(B), —SR, —CN,—N₃ and

wherein

represents a three to eight membered heterocyclyl group bound at the Natom, wherein the heterocyclyl group is saturated, partially unsaturatedor aromatic; when the heterocyclyl group is a saturated six to eightmembered heterocyclyl, the heterocyclyl group may optionally contains agroup selected from O, CHR, NR, S, SO, or SO₂, provided that that thegroup is separated from the N atom by at least two carbon atoms; andwherein the heterocyclyl group is optionally substituted with one ormore substituents independently selected from R; R³is selected from thegroup consisting of hydrogen, alkyl, aralkyl, cycloalkyl, fluorinatedalkyl, —COR, —COOR and —CONR^(C)R^(D); wherein the aralkyl may beoptionally substituted with one or more substituents independentlyselected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino,mono- or di-substituted amino, cyano or nitro; R⁴ is selected from thegroup consisting of, alkyl, aryl, aralkyl, cycloalkyl, fluorinatedalkyl, alkenyl, alkynyl, —COOR, —COR, —CONR^(C) R^(D), -alkyl—COOR,heterocyclyl and

wherein the alkyl, alkenyl, alkynyl, aryl, aralkyl or heterocyclyl maybe optionally substituted with one or more substituents independentlyselected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, aryl,amino, mono-or di-substituted amino, cyano or nitro; and where Y isselected from the group consisting of O, S and NR^(A); where R isselected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl,adamantyl, norbornyl, fluorinated alkyl and heterocycle; wherein thearyl, aralkyl or heterocycle may be optionally substituted with one ormore substituents independently selected from halogen, hydroxy, alkyl,halogenated alkyl, alkoxy, amino, mono-or di-substituted amino, cyano ornitro; where R^(A) and R^(B) are independently selected from the groupconsisting of hydrogen, —R, —COOR, —COR, —SO₂R, —SOR and —CONR^(C)R^(D)and

where R^(C) and R^(D) are independently selected from the groupconsisting of hydrogen, alkyl, aryl, aralkyl, cycloalkyl, fluorinatedalkyl and heterocycle; wherein the aryl, aralkyl or heterocycle may beoptionally substituted with one or more substituents independentlyselected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino,mono-or di-substituted amino, cyano or nitro; or are joined together toform a 4 to 8 membered heterocyclyl ring structure; which methodcomprises reacting a compound of formula (III)

with a compound of formula (IV)

wherein A is selected from F, Cl, Br or —OC(O)-t-butyl, and wherein V isa sterically hindered group, in a non-protic solvent; and then reactingwith a compound of formula (V)

wherein W is selected from the group consisting of —O, —NSd₂R, —NSOR,—NCOR, —NCOOR, —NCOR^(C)R^(D) and —NR to form the corresponding compoundof formula (Ic)

and optionally reacting the compound of formula (Ic) with a compound offormula (VI) Z—H   (VI) wherein Z is as previously defined, to yield thecorresponding compound of formula (Ia).
 2. The process of claim 1wherein V is selected from the group consisting of t-butyl, O-t-butyl,O-isopropyl, O-adamantyl, adamantyl, N(alkyl)₂, N(aryl)₂,2,6-dimethylphenyl, 2,6-disubstituted phenyl.
 3. The process of claim 1wherein the non-protic solvent is selected from the group consisting ofacetonitrile, dioxane and THF.
 4. A process for preparing a compound ofgeneral formula (Ia):

wherein X is selected from the group consisting of NH, NR^(A) and S;

represents a 5 membered aromatic ring structure; optionally containingone to two additional heteroatoms selected from the group consisting ofN, O and S; provided that the additional heteroatoms are not at theattachment point of the

group; provided that the 5 membered ring remains aromatic in nature;wherein the 5 membered ring is optionally substituted with one to threesubstituents independently selected from the group consisting ofhalogen, hydroxy, alkyl, halogenated alkyl, alkenyl, cycloalkyl, alkoxy,aryl, aralkyl, heterocyclyl, amino, mono-or di-substituted amino, cyano, nitro, —COOR, —COR, —SO₂R and —CONR^(B)R^(C); wherein the aminesubstituents are independently selected from alkyl, cycloalkyl, aryl oraralkyl; wherein the cycloalkyl, aryl or heterocyclyl may be furtheroptionally substituted with one or more substituent is independentlyselected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino,mono-or di-substituted amino, cyano or nitro; Z is hydrogen; R³ isselected from the group consisting of hydrogen, alkyl, aralkyl,cycloalkyl, fluorinated alkyl, —COR, —COOR and —CONR^(C)R^(D); whereinthe aralkyl may be optionally substituted with one or more substituentsindependently selected from halogen, hydroxy, alkyl, halogenated alkyl,alkoxy, amino, mono- or di-substituted amino, cyano or nitro; R⁴ isselected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl,fluorinated alkyl, alkenyl, alkynyl, —COOR, —COR, —CONR^(C)R^(D),-alkyl—COOR, heterocyclyl and

wherein the alkyl, alkenyl, alkynyl, aryl, aralkyl or heterocyclyl maybe optionally substituted with one or more substituents independentlyselected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, aryl,amino, mono-or di-substituted amino, cyano or nitro; and where Y isselected from the group consisting of O, S and NR^(A); where R isselected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl,adamantyl, norbornyl, fluorinated alkyl and heterocycle; wherein thearyl, aralkyl or heterocycle may be optionally substituted with one ormore substituents independently selected from halogen, hydroxy, alkyl,halogenated alkyl, alkoxy, amino, mono-or di-substituted amino, cyano ornitro; where R^(A) and R^(B) are independently selected from the groupconsisting of hydrogen, —R, —COOR, —COR, —SO₂R, —SOR and —CONR^(C)R^(D)and

where R^(C) and R^(D) are independently selected from the groupconsisting of hydrogen, alkyl, aryl, aralkyl, cycloalkyl, fluorinatedalkyl and heterocycle; wherein the aryl, aralkyl or heterocycle may beoptionally substituted with one or more substituents independentlyselected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino,mono-or di-substituted amino, cyano or nitro; or are joined together toform a 4 to 8 membered heterocyclyl ring structure; which methodcomprises reacting a compound of formula (III)

with a compound of formula (IV)

wherein A is selected from F, Cl, Br or —OC(O)-t-butyl, and wherein V isa sterically hindered group, in a non-protic solvent; and then reactingwith a compound of formula (V)

wherein W is selected from the group consisting of ONSO₂R, —NSOR, —NCOR,—NCOOR, —NCOR^(C)R^(D), —NOCOR and NR to form the corresponding compoundof formula (Ic)

and reacting the compound of formula (Ic) with hydrogen gas, in thepresence of a metal catalyst, to yield the corresponding compound offormula (Ia).
 5. A method of synthesizing highly substituted azolecompounds having the general formula (IIa):

wherein X is selected from the group consisting of NH, NR^(A) and S;

represents a 9 membered ring structure, wherein the five memberedportion of the ring structure

aromatic and the six membered portion of the ring structure

is saturated, partially unsaturated, or aromatic; wherein the 5 memberedportion of the ring structure is optionally substituted with one to twosubstituents independently selected from the group consisting ofhalogen, hydroxy, alkyl, alkenyl, halogenated alkyl, cycloalkyl, alkoxy,aryl, aralkyl, heterocyclyl, amino, mono-or di-substituted amino, cyano,nitro, —COOR, —COR, —SO₂R and —CONR^(B)R^(C); wherein the aminesubstituents are independently selected from alkyl, cycloalkyl, aryl oraralkyl; wherein the cycloalkyl, aryl or heterocyclyl may be furtheroptionally substituted with one or more substituent is independentlyselected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino,mono-or di-substituted amino, cyano or nitro; wherein the 6-memberedportion of the ring structure may further optionally containing one tofour additional heteroatoms selected from the group consisting of N, Oand S; wherein the 6-membered portion of the ring structure may furtherbe optionally substituted with one to four substituents independentlyselected from the group consisting of halogen, hydroxy, alkyl,halogenated alkyl, cycloalkyl, alkoxy, aryl, aralkyl, heterocyclyl,amino, mono-or di-substituted amino, cyano, nitro, —COOR, —COR, —SO₂Rand —CONR^(B)R^(C); wherein the amine substituents are independentlyselected from alkyl, cycloalkyl, aryl or aralkyl; wherein thecycloalkyl, aryl or heterocyclyl may be further optionally substitutedwith one or more substituent independently selected from halogen,hydroxy, alkyl, halogenated alkyl, alkoxy, amino, mono-or di-substitutedamino, cyano or nitro; Z is selected from the group consisting of—OR^(A), —NR^(A) R^(B), —N(R^(A))OR^(B), —SR, —CN, —N₃ and

wherein

represents a three to eight membered heterocyclyl group bound at the Natom, wherein the heterocyclyl group is saturated, partially unsaturatedor aromatic; when the heterocyclyl group is a saturated six to eightmembered heterocyclyl, the heterocyclyl group may optionally contains agroup selected from O, CHR, NR, S, SO, or SO₂,provided that that thegroup is separated from the N atom by at least two carbon atoms; adnwherein the heterocyclyl group is optionally substituted with one ormore substituents independently selected from R; R³ is selected from thegroup consisting of hydrogen, alkyl, aralkyl, cycloalkyl, fluorinatedalkyl, —COR, —COOR and —CONR^(C)R^(D); wherein the aralkyl may beoptionally substituted with one or more substituents independentlyselected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino,mono- or di-substituted amino, cyano or nitro; R⁴ is selected from thegroup consisting of, alkyl, aryl, aralkyl, cycloalkyl, fluorinatedalkyl, alkenyl, alkynyl, —COOR, —COR, —CONR^(C)R^(D), -alkyl—COOR,heterocyclyl and

wherein the alkyl, alkenyl, alkynyl, aryl, aralkyl or heterocyclyl maybe optionally substituted with one or more substituents independentlyselected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, aryl,amino, mono-or di-substituted amino, cyano or nitro; and where Y isselected from the group consisting of O, S and NR^(A); where R isselected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl,adamantyl, norbornyl, fluorinated alkyl and heterocycle; wherein thearyl, aralkyl or heterocycle may be optionally substituted with one ormore substituents independently selected from halogen, hydroxy, alkyl,halogenated alkyl, alkoxy, amino, mono-or di-substituted amino, cyano ornitro; where R^(A) and R^(B) are independently selected from the groupconsisting of hydrogen, —R, —COOR, —COR, —SO₂R, —SOR and —CONR^(C)R^(D)and

where R^(C) and R^(D) are independently selected from the groupconsisting of hydrogen, alkyl, aryl, aralkyl, cycloalkyl, fluorinatedalkyl and heterocycle; wherein the aryl, aralkyl or heterocycle may beoptionally substituted with one or more substituents independentlyselected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino,mono-or di-substituted amino, cyano or nitro; or are joined together toform a 4 to 8 membered heterocyclyl ring structure; which methodcomprises reacting a compound of formula (VII)

with a compound of formula (IV)

wherein A is selected from F, Cl, Br or OC(O)-t-butyl, and wherein V isa sterically hindered group, in a non-protic solvent; and then reactingwith a compound of formula (V)

wherein W is selected from the group consisting of ONSO₂R, —NSOR, —NCOR,—NCOOR, —NCOR^(C)R^(D), —NOCOR and NR to form the corresponding compoundof formula (IIc)

and optionally reacting the compound of formula (IIc) with a compound offormula (VI) Z—H  (VI) wherein Z is as previously defined, to yield thecorresponding compound of formula (IIa).
 6. The process of claim 5wherein V is selected from the group consisting of t-butyl, O-t-butyl,O-isoproyl and O-adamantyl, adamantyl, N(alkyl)₂, N(aryl)₂,2,6-dimethylphenyl, 2,6-disubstituted phenyl.
 7. The process of claim 5wherein the non-protic solvent is selected from the group consisting ofacetonitrile, dioxane and THF.
 8. A method of synthesizing highlysubstituted azole compounds having the general formula (IIa):

wherein X is selected from the group consisting of NH, NR^(A) and S;

represents a 9 membered ring structure, wherein the five memberedportion of the ring structure

is aromatic and the six membered portion of the ring structure

is saturated, partially unsaturated, or aromatic; wherein the 5 memberedportion of the ring structure is optionally substituted with one to twosubstituents independently selected from the group consisting ofhalogen, hydroxy, alkyl, alkenyl, halogenated alkyl, cycloalkyl, alkoxy,aryl, aralkyl, heterocyclyl, amino, mono-or di-substituted amino, cyano,nitro, —COOR, —COR, —SO₂R and —CONR^(B)R^(C); wherein the aminesubstituents are independently selected from alkyl, cycloalkyl, aryl oraralkyl; wherein the cycloalkyl, aryl or heterocyclyl may be furtheroptionally substituted with one or more substituent is independentlyselected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino,mono-or di-substituted amino, cyano or nitro; wherein the 6-memberedportion of the ring structure may further optionally containing one tofour additional heteroatoms selected from the group consisting of N, Oand S; wherein the 6-membered portion of the ring structure may furtherbe optionally substituted with one to four substituents independentlyselected from the group consisting of halogen, hydroxy, alkyl,halogenated alkyl, cycloalkyl, alkoxy, aryl, aralkyl, heterocyclyl,amino, mono-or di-substituted amino, cyano, nitro, —COOR, —COR, —SO₂Rand —CONR^(B)R^(C); wherein the amine substituents are independentlyselected from alkyl, cycloalkyl, aryl or aralkyl; wherein thecycloalkyl, aryl or heterocyclyl may be further optionally substitutedwith one or more substituent independently selected from halogen,hydroxy, alkyl, halogenated alkyl, alkoxy, amino, mono-or di-substitutedamino, cyano or nitro; Z is hydrogen; R³ is selected from the groupconsisting of hydrogen, alkyl, aralkyl, cycloalkyl, fluorinated alkyl,—COR, —COOR and —CONR^(C)R^(D); wherein the aryl, aralkyl orheterocyclyl may be optionally substituted with one or more substituentsindependently selected from halogen, hydroxy, alkyl, halogenated alkyl,alkoxy, amino, mono-or di-substituted amino, cyano or nitro; R⁴ isselected from the group consisting of, alkyl, aryl, aralkyl, cycloalkyl,fluorinated alkyl, alkenyl, alkynyl, —COR, —COOR, —CONR^(C)R^(D),-alkyl—COOR, heterocyclyl and

wherein the alkyl, alkenyl, alkynyl, aryl, aralkyl or heterocyclyl maybe optionally substituted with one or more substituents independentlyselected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, aryl,amino, mono-or di-substituted amino, cyano or nitro; and where Y isselected from the group consisting of O, S and NR^(A); where R isselected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl,adamantyl, norbornyl, fluorinated alkyl and heterocycle; wherein thearyl, aralkyl or heterocycle may be optionally substituted with one ormore substituents independently selected from halogen, hydroxy, alkyl,halogenated alkyl, alkoxy, amino, mono-or di-substituted amino, cyano ornitro; where R^(A) and R^(B) are independently selected from the groupconsisting of hydrogen, —R, —COOR, —COR, —SO₂R, —SOR and —CONR^(C)R^(D)and

where R^(C) and R^(D) are independently selected from the groupconsisting of hydrogen, alkyl, aryl, aralkyl, cycloalkyl, fluorinatedalkyl and heterocycle; wherein the aryl, aralkyl or heterocycle may beoptionally substituted with one or more substituents independentlyselected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino,mono-or di-substituted amino, cyano or nitro; or are joined together toform a 4 to 8 membered heterocyclyl ring structure; which methodcomprises reacting a compound of formula (VII)

with a compound of formula (IV)

wherein A is selected from F, Cl, Br or OC(O)-t-butyl, and wherein V isa sterically hindered group, in a non-protic solvent; and then reactingwith a compound of formula (V)

wherein W is selected from the group consisting of ONSO₂R, —NSOR, —NCOR,—NCOOR, —NCOR^(C)R^(D), —NOCOR and NR, to form the correspondingcompound of formula (IIc)

and optionally reacting the compound of formula (IIc) with hydrogen gas,in the presence of a metal catalyst, to yield the corresponding compoundof formula (IIa).
 9. A method for preparing compounds of the formula(Ib)

wherein X is selected from the group consisting of NH, NR^(A) and S;

represents a 5 membered aromatic ring structure; optionally containingone to two additional heteroatoms selected from the group consisting ofN, O and S; provided that the additional heteroatoms are not at theattachment point of the —C(O)NR⁵R⁶group; provided that the 5 memberedring remains aromatic in nature; wherein the 5 membered ring isoptionally substituted with one to three substituents independentlyselected from the group consisting of halogen, hydroxy, alkyl,halogenated alkyl, alkenyl, cycloalkyl, alkoxy, aryl, aralkyl,heterocyclyl, amino, mono-or di-substituted amino, cyano , nitro, —COOR,—COR, —SO₂R and —CONR BR^(C); wherein the amine substituents areindependently selected from alkyl, cycloalkyl, aryl or aralkyl; whereinthe cycloalkyl, aryl or heterocyclyl may be further optionallysubstituted with one or more substituent is independently selected fromhalogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino, mono-ordi-substituted amino, cyano or nitro; R⁵ is selected from the groupconsisting of hydrogen, alkyl, aryl, aralkyl, cycloalkyl, fluorinatedalkyl and heterocyclyl; wherein the aryl, aralkyl or heterocyclyl may beoptionally substituted with one or more substituents independentlyselected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino,mono-or di-substituted amino, cyano or nitro; R⁶ is selected from thegroup consisting of hydrogen, alkyl, aralkyl, cycloalkyl, —COOR, —COR,—SO₂R, —CONR^(C)R^(D) and

where R is selected from the group consisting of alkyl, aryl, aralkyl,cycloalkyl, adamantyl, norbornyl, fluorinated alkyl and heterocycle;wherein the aryl, aralkyl or heterocycle may be optionally substitutedwith one or more substituents independently selected from halogen,hydroxy, alkyl, halogenated alkyl, alkoxy, amino, mono-or di-substitutedamino, cyano or nitro; where R^(A) and R^(B) are independently selectedfrom the group consisting of hydrogen, —R, —COOR, —COR, —SO₂R, —SOR and—CONR^(C)R^(D) and

where R^(C) and R^(D) are independently selected from the groupconsisting of hydrogen, alkyl, aryl, aralkyl, cycloalkyl, fluorinatedalkyl and heterocycle; wherein the aryl, aralkyl or heterocycle may beoptionally substituted with one or more substituents independentlyselected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino,mono-or di-substituted amino, cyano or nitro; or are joined together toform a 4 to 8 membered heterocyclyl ring structure; which methodcomprises reacting a compound of formula (III)

with a compound of formula (IV)

wherein A is selected from F, Cl, Br or OC(O)-t-butyl, and wherein V isa sterically hindered group, in a non-protic solvent; and then reactingwith a compound of formula (VIII) R⁵—N═C═O   (VIII) wherein R⁵ is aspreviously defined, to yield the compound of formula

reacting the compound of formula (I) with an inorganic base to yield thecompound of formula (Ie)

optionally reacting the compound of formula (Ie) with a compound offormula (IX) R⁶—Q   (IX) wherein Q is selected from the group consistingof chlorine, bromine and iodine, in the presence of a base, to yield thecorresponding compound of formula (Ib).
 10. The process of claim 9wherein V is selected from the group consisting of t-butyl, O-t-butyl,O-isopropyl, O-adamantyl adamantyl, N(alkyl)₂, N(aryl)₂,2,6-dimethylphenyl, 2,6-disubstituted phenyl.
 11. The process of claim 9wherein the non-protic solvent is selected from the group consisting ofacetonitrile, dioxane and THF.
 12. A method for preparing compounds ofthe formula (IIb)

wherein X is selected from the group consisting of NH, NR^(A) and S;

represents a 9 membered ring structure, wherein the five memberedportion of the ring structure

is aromatic and the six membered portion of the ring structure

is saturated, partially unsaturated, or aromatic; wherein the 5 memberedportion of the ring structure is optionally substituted with one to twosubstituents independently selected from the group consisting ofhalogen, hydroxy, alkyl, alkenyl, halogenated alkyl, cycloalkyl, alkoxy,aryl, aralkyl, heterocyclyl, amino, mono-or di-substituted amino, cyano,nitro, —COOR, —COR, —SO₂R and —CONR^(B)R^(C); wherein the aminesubstituents are independently selected from alkyl, cycloalkyl, aryl oraralkyl; wherein the cycloalkyl, aryl or heterocyclyl may be furtheroptionally substituted with one or more substituent is independentlyselected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino,mono-or di-substituted amino, cyano or nitro; wherein the 6-memberedportion of the ring structure may further optionally containing one tofour additional heteroatoms selected from the group consisting of N, Oand S; wherein the 6-membered portion of the ring structure may furtherbe optionally substituted with one to four substituents independentlyselected from the group consisting of halogen, hydroxy, alkyl,halogenated alkyl, cycloalkyl, alkoxy, aryl, aralkyl, heterocyclyl,amino, mono-or di-substituted amino, cyano, nitro, —COOR, —COR, —SO₂Rand —CONR^(B)R^(C); wherein the amine substituents are independentlyselected from alkyl, cycloalkyl, aryl or aralkyl; wherein thecycloalkyl, aryl or heterocyclyl may be further optionally substitutedwith one or more substituent independently selected from halogen,hydroxy, alkyl, halogenated alkyl, alkoxy, amino, mono-or di-substitutedamino, cyano or nitro; R⁵ is selected from the group consisting ofhydrogen, alkyl, aryl, aralkyl, cycloalkyl, fluorinated alkyl andheterocyclyl; wherein the aryl, aralkyl or heterocyclyl may beoptionally substituted with one or more substituents independentlyselected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino,mono-or di-substituted amino, cyano or nitro; R⁶ is selected from thegroup consisting of hydrogen, alkyl, aralkyl, cycloalkyl, —COOR, —COR,—SO₂R, —CONR^(C)R^(D) and

where R is selected from the group consisting of alkyl, aryl, aralkyl,cycloalkyl, adamantyl, norbornyl, fluorinated alkyl and heterocycle;wherein the aryl, aralkyl or heterocycle may be optionally substitutedwith one or more substituents independently selected from halogen,hydroxy, alkyl, halogenated alkyl, alkoxy, amino, mono-or di-substitutedamino, cyano or nitro; where R^(A) and R⁸ are independently selectedfrom the group consisting of hydrogen, —R, —COOR, —COR, —SO₂R, —SOR and—CONR^(C)R^(D) and

where R^(C) and R^(D) are independently selected from the groupconsisting of hydrogen, alkyl, aryl, aralkyl, cycloalkyl, fluorinatedalkyl and heterocycle; wherein the aryl, aralkyl or heterocycle may beoptionally substituted with one or more substituents independentlyselected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino,mono-or di-substituted amino, cyano or nitro; or are joined together toform a 4 to 8 membered heterocyclyl ring structure; which methodcomprises reacting a compound of formula (VII)

with a compound of formula (IV)

wherein A is selected from F, Cl, Br or OC(O)-t-butyl, and wherein V isa sterically hindered group, in a non-protic solvent; and then reactingwith a compound of formula (VIII) R⁵—N═C═O   (VIII) wherein R⁵is aspreviously defined, to yield the compound of formula (IId)

reacting the compound of formula (IId) with an inorganic base to yieldthe compound of formula (IIe)

optionally reacting the compound of formula (lie) with a compound offormula (IX) R⁶—Q   (IX) wherein Q is selected from the group consistingof chlorine, bromine and iodine, in the presence of a base, to yield thecorresponding compound of formula (IIb).
 13. The process of claim 9wherein V is selected from the group consisting of t-butyl, O-t-butyl,O-isopropyl, O-adamantyl, adamantyl, N(alkyl)₂, N(aryl)₂,2,6-dimethylphenyl, 2,6-disubstituted phenyl.
 14. The process of claim 9wherein the non-protic solvent is selected from the group consisting ofacetonitrile, dioxane and THF.
 15. A chemical library comprising aplurality of substituted azoles compounds prepared by the method ofclaim
 1. 16. A chemical library comprising a plurality of substitutedazoles compounds prepared by the method of claim
 4. 17. A chemicallibrary comprising a plurality of substituted azoles compounds preparedby the method of claim
 5. 18. A chemical library comprising a pluralityof substituted azoles compounds prepared by the method of claim
 8. 19. Achemical library comprising a plurality of substituted azoles compoundsprepared by the method of claim
 9. 20. A chemical library comprising aplurality of substituted azoles compounds prepared by the method ofclaim
 12. 21. The process of claim 1 wherein

is selected from the group consisting of imidazolyl, substitutedimidazolyl (wherein the substituents on the imidazolyl group are one ormore independently selected from halogen, alkyl, aryl, aralkyl,cycloalkyl, or alkoxycarbonyl, —C(O)N(alkyl)₂), thiazolyl, substitutedthiazolyl (wherin the substituents on the thiazolyl group are one ormore independently selected from alkyl and alkenyl),2-aralkyl-substituted-4H-1,2,4-triazolyl and 4-aralkylsubstituted-4H-1,2,4-triazolyl; Z is selected from the group consistingof—OC(O)N(alkyl)₂, —N(aryl)C(O)N(alkyl)₂, —N(aralkyl)C(O)N(alkyl)₂,—N(aralkyl)C(O)O(alkyl), —N(aralkyl)C(O)O-adamantyl,—N(SO₂aryl)C(O)N(alkyl)₂, —N(SO₂aryl)C(O)O(alkyl), —N(SO₂alkylsubstituted aryl)C(O)O(alkyl), —N(C(O)N(alkyl)₂)OC(O)(alkyl),—OC(O)O(alkyl), —OC(O)(aryl), —OH, -alkoxy, —N₃, —NHC(O)-alkyl,—NH(alkyl), —NH(hydroxy substituted alkyl), —NH(alkoxy), —NH(aryl),—NH(aralkyl), —NH-(heterocyclyl), —NHSO₂-alkyl, —SH-aryl, —SH-alkyl,—SH-(amino substituted alkyl) and heterocyclyl; R³ is selected from thegroup consisting of hydrogen, alkyl, trifluoromethyl and —C(O)O-alkyl;and R⁴ is selected from the group consisting of alkyl, alkenyl,cycloalkyl, aryl, substituted aryl (where the aryl substituent isselected from halogen, alkyl, alkoxy, nitro, amino, alkylamino ordialkylamino), aralkyl, -(alkyl)—C(O)O—(alkyl),

pyridinyl, —C(O)-aryl and —C(O)O-alkyl.
 22. The process of claim 21wherein

is selected from the group consisting of 1-imidazolyl,1-methyl-imidazolyl, 1-phenyl-imidazolyl, 1-benzyl-imidazolyl,1-(di(i-propyl)aminocarbonyl)-imidazolyl, 1-methyl-5-chloro-imidazolyl,1-methyl-4,5-dichloro-imidazolyl, 1-methyl-5-methoxycarbonyl-imidazolyl,thiazolyl, 4,5-dimethyl-thiazolyl, 4-methyl-5-vinyl-thiazolyl,2-benzyl-4H-1,2,4-triazolyl and 4-benzyl-4H-1,2,4-triazolyl; Z isselected from the group consisting of —OC(O)N(methyl)₂,—OC(O)N(ethyl)₂,—OC(O)N(i-propyl)₂, —N(phenyl)C(O)N(i-propyl)₂,—N(benzyl)C(O)O-t-butyl, —N(benzyl)C(O)O-adamantyl,N(benzyl)C(O)N(i-propyl)₂, —N(SO₂-phenyl)C(O)N(i-propyl)₂,—N(SO₂phenyl)C(O)O-t-butyl, —N(SO₂-P-toluenyl)C(O)Ot-butyl,—N(C(O)N(i-propyl)₂)OC(O)methyl, —OC(O)O(t-butyl), —OC(O)(phenyl), —OH,—OCH₃, —OCH₂CH₃, —N₃, —NH—C(O)CH₃, —NH—SO₂CH₃, —NH—OCH₃, —NH—CH₂CH₂OH,—NH-phenyl, —NH-benzyl, —NH-pyridin-2-yl, —S-phenyl, —S—CH₂CH₂NH₂,morpholin-1-yl, piperidin-1-yl, 4-methyl-piperazin-1-yl andimidazol-1-yl; R³ is selected from the group consisting of hydrogen,methyl, trifluoromethyl and —C(O)OCH₂CH₃; and R⁴ is selected from thegroup consisting of methyl, ethyl, t-butyl, i-propyl, cyclohexyl,phenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-nitrophenyl, benzyl,phenylethyl, —CH═CH₂, —CH═CHCH₃,

2-pyridinyl, —C(O)-phenyl and —C(O)OCH₂CH₃.
 23. The process of claim 5wherein

is selected from the group consisting of 1-substituted-benzimidazolyl(where the substituent on the benzimidazolyl group is selected from H,alkyl, aryl, aralkyl, cycloalkyl or—C(O)N(alkyl)₂), and benzthiazolyl; Zis selected from the group consisting of —OH and —OC(O)N(alkyl)₂; R³ishydrogen; and R⁴ is aryl.
 24. The process of claim 23 wherein

is selected from the group consisting of 1-methyl-benzimidazolyl andbenzthiazolyl; Z is selected from the group consisting of—OH,—OC(O)N(methyl)₂ and —OC(O)N(i-propyl)₂; R³ is hydrogen; and R⁴ isphenyl.
 25. The process of claim 9 wherein

is selected from the group consisting of 1-substituted imidazolyl (wherethe substituent on the imidazolyl group is selected from H, alkyl, aryl,aralkyl, cycloalkyl or —C(O)N(alkyl)₂) and thiazolyl; R⁵ is selectedfrom the group consisting of aryl, alkyl, aralkyl and cycloalkyl; and R⁶is selected from the group consisting of—C(O)N(alkyl)₂.
 26. The processof claim 25 wherein

1-benzyl-imidazolyl; R⁵ isphenyl; and R⁶ is —C(O)N(i-propyl)₂.
 27. Aprocess for preparing a compound of general formula (Ic):

wherein X is selected from the group consisting of NH, NR^(A) and S;

represents a 5 membered aromatic ring structure; optionally containingone to two additional heteroatoms selected from the group consisting ofN, O and S; provided that the additional heteroatoms are not at theattachment point of the

group; provided that the 5 membered ring remains aromatic in nature;wherein the 5 membered ring is optionally substituted with one to threesubstituents independently selected from the group consisting ofhalogen, hydroxy, alkyl, halogenated alkyl, alkenyl, cycloalkyl, alkoxy,aryl, aralkyl, heterocyclyl, amino, mono-or di-substituted amino, cyano,nitro, —COOR, —COR, —SO₂R and —CONR^(B)R^(C); wherein the aminesubstituents are independently selected from alkyl, cycloalkyl, aryl oraralkyl; wherein the cycloalkyl, aryl or heterocyclyl may be furtheroptionally substituted with one or more substituent is independentlyselected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino,mono-or di-substituted amino, cyano or nitro; W is selected from thegroup consisting of —O, —NSO₂R, —NSOR, —NCOR, —NCOOR,—NCONR^(C) R^(D),—NOCOR and —NR; V is selected from the group consisting of t-butyl,adamantyl, —N(alkyl)₂, —N(aryl)₂, 2,6,-dimethylphenyl, 2,6-disubstitutedphenyl (wherein the substituents are selected from halogen, alkyl oralkoxy), —O—t-butyl, —O—1-propyl and —O— adamantyl; R³ is selected fromthe group consisting of hydrogen, alkyl, aralkyl, cycloalkyl,fluorinated alkyl, —COR, —COOR and —CONR^(C)R^(D); wherein the aralkylmay be optionally substituted with one or more substituentsindependently selected from halogen, hydroxy, alkyl, halogenated alkyl,alkoxy, amino, mono- or di-substituted amino, cyano or nitro; R⁴ isselected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl,fluorinated alkyl, alkenyl, alkynyl, —COOR, —COR, —CONR^(C)R^(D),-alkyl—COOR, heterocyclyl and

wherein the alkyl, alkenyl, alkynyl, aryl, aralkyl or heterocyclyl maybe optionally substituted with one or more substituents independentlyselected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, aryl,amino, mono-or di-substituted amino, cyano or nitro; and where Y isselected from the group consisting of O, S and NR^(A); where R isselected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl,adamantyl, norbornyl, fluorinated alkyl and heterocycle; wherein thearyl, aralkyl or heterocycle may be optionally substituted with one ormore substituents independently selected from halogen, hydroxy, alkyl,halogenated alkyl, alkoxy, amino, mono-or di-substituted amino, cyano ornitro; where R^(A) and R^(B) are independently selected from the groupconsisting of hydrogen, —R, —COOR, —COR, —SO₂R, —SOR and —CONR^(C)R^(D)and

where R^(C) and R^(D) are independently selected from the groupconsisting of hydrogen, alkyl, aryl, aralkyl, cycloalkyl, fluorinatedalkyl and heterocycle; wherein the aryl, aralkyl or heterocycle may beoptionally substituted with one or more substituents independentlyselected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino,mono-or di-substituted amino, cyano or nitro; or are joined together toform a 4 to 8 membered heterocyclyl ring structure; which methodcomprises reacting a compound of formula (III)

with a compound of formula (IV)

wherein A is selected from F, Cl, Br or —OC(O)-t-butyl, and wherein V isa sterically hindered group, in a non-protic solvent; and then reactingwith a compound of formula (V)

wherein W is selected from the group consisting of ONSO₂R, —NSOR, —NCOR,—NCOOR, —NCOR^(C)R^(D), —NOCOR and NR to form the corresponding compoundof formula (Ic).
 28. A process for preparing a compound of the generalformula (IIc)

wherein X is selected from the group consisting of NH, NR^(A) and S;

represents a 9 membered ring structure, wherein the five memberedportion of the ring structure

is aromatic and the six membered portion of the ring structure

is saturated, partially unsaturated, or aromatic; wherein the 5 memberedportion of the ring structure is optionally substituted with one to twosubstituents independently selected from the group consisting ofhalogen, hydroxy, alkyl, alkenyl, halogenated alkyl, cycloalkyl, alkoxy,aryl, aralkyl, heterocyclyl, amino, mono-or di-substituted amino, cyano,nitro, —COOR, —COR, —SO₂R and —CONR^(B)R^(C); wherein the aminesubstituents are independently selected from alkyl, cycloalkyl, aryl oraralkyl; wherein the cycloalkyl, aryl or heterocyclyl may be furtheroptionally substituted with one or more substituent is independentlyselected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino,mono-or di-substituted amino, cyano or nitro; wherein the 6-memberedportion of the ring structure may further optionally containing one tofour additional heteroatoms selected from the group consisting of N, Oand S; wherein the 6-membered portion of the ring structure may furtherbe optionally substituted with one to four substituents independentlyselected from the group consisting of halogen, hydroxy, alkyl,halogenated alkyl, cycloalkyl, alkoxy, aryl, aralkyl, heterocyclyl,amino, mono-or di-substituted amino, cyano, nitro, —COOR, —COR, —SO₂Rand —CONR^(B)R^(C); wherein the amine substituents are independentlyselected from alkyl, cycloalkyl, aryl or aralkyl; wherein thecycloalkyl, aryl or heterocyclyl may be further optionally substitutedwith one or more substituent independently selected from halogen,hydroxy, alkyl, halogenated alkyl, alkoxy, amino, mono-or di-substitutedamino, cyano or nitro; W is selected from the group consisting of —O,—NSO₂R, —NSOR, —NCOR, —NCOOR, NCONR^(C) R^(D), —NOCOR and —NR; V isselected from the group consisting of t-butyl, adamantyl, —N(alkyl)₂,—N(aryl)₂, 2,6,-dimethylphenyl, 2,6-disubstituted phenyl (wherein thesubstituents are selected from halogen, alkyl or alkoxy), —O—t-butyl,—O—1-propyl and —O— adamantyl; R³ is selected from the group consistingof hydrogen, alkyl, aralkyl, cycloalkyl, fluorinated alkyl, —COR, —COORand —CONR^(C)R^(D); wherein the aryl, aralkyl or heterocyclyl may beoptionally substituted with one or more substituents independentlyselected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino,mono-or di-substituted amino, cyano or nitro; R⁴ is selected from thegroup consisting of, alkyl, aryl, aralkyl, cycloalkyl, fluorinatedalkyl, alkenyl, alkynyl, —COR, —COOR, —CONR^(C)R^(D), -alkyl—COOR,heterocyclyl and

wherein the alkyl, alkenyl, alkynyl, aryl, aralkyl or heterocyclyl maybe optionally substituted with one or more substituents independentlyselected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, aryl,amino, mono-or di-substituted amino, cyano or nitro; and where Y isselected from the group consisting of O, S and NR^(A); where R isselected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl,adamantyl, norbornyl, fluorinated alkyl and heterocycle; wherein thearyl, aralkyl or heterocycle may be optionally substituted with one ormore substituents independently selected from halogen, hydroxy, alkyl,halogenated alkyl, alkoxy, amino, mono-or di-substituted amino, cyano ornitro; where R^(A) and R^(B) are independently selected from the groupconsisting of hydrogen, —R, —COOR, —COR, —SO₂R, —SOR and —CONR^(C)R^(D)and

where R^(C) and R^(D) are independently selected from the groupconsisting of hydrogen, alkyl, aryl, aralkyl, cycloalkyl, fluorinatedalkyl and heterocycle; wherein the aryl, aralkyl or heterocycle may beoptionally substituted with one or more substituents independentlyselected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino,mono-or di-substituted amino, cyano or nitro; or are joined together toform a 4 to 8 membered heterocyclyl ring structure; which methodcomprises reacting a compound of formula (VII)

with a compound of formula (IV)

wherein A is selected from F, Cl, Br or OC(O)-t-butyl, and wherein V isa sterically hindered group, in a non-protic solvent; and then reactingwith a compound of formula (V)

wherein W is selected from the group consisting of ONSO₂R, —NSOR, —NCOR,—NCOOR, —NCOR^(C)R^(D), —NOCOR and NR, to form the correspondingcompound of formula (IIc).
 29. A method for preparing compounds of theformula (Id)

wherein X is selected from the group consisting of NH, NR^(A) and S;

represents a 5 membered aromatic ring structure; optionally containingone to two additional heteroatoms selected from the group consisting ofN, O and S; provided that the additional heteroatoms are not at theattachment point of the —C(O)NR⁵R⁶ group; provided that the 5 memberedring remains aromatic in nature; wherein the 5 membered ring isoptionally substituted with one to three substituents independentlyselected from the group consisting of halogen, hydroxy, alkyl,halogenated alkyl, alkenyl, cycloalkyl, alkoxy, aryl, aralkyl,heterocyclyl, amino, mono-or di-substituted amino, cyano , nitro, —COOR,—COR, —SO₂R and —CONR^(B)R^(C); wherein the amine substituents areindependently selected from alkyl, cycloalkyl, aryl or aralkyl; whereinthe cycloalkyl, aryl or heterocyclyl may be further optionallysubstituted with one or more substituent is independently selected fromhalogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino, mono-ordi-substituted amino, cyano or nitro; V is selected from the groupconsisting of t-butyl, adamantyl, —N(alkyl)₂, —N(aryl)₂,2,6,-dimethylphenyl, 2,6-disubstituted phenyl (wherein the substituentsare selected from haloge, alkyl or alkoxy), —O—t-butyl, —O—i-propyl and—O— adamantyl; R⁵ is selected from the group consisting of hydrogen,alkyl, aryl, aralkyl, cycloalkyl, fluorinated alkyl and heterocyclyl;wherein the aryl, aralkyl or heterocyclyl may be optionally substitutedwith one or more substituents independently selected from halogen,hydroxy, alkyl, halogenated alkyl, alkoxy, amino, mono-or di-substitutedamino, cyano or nitro; where R is selected from the group consisting ofalkyl, aryl, aralkyl, cycloalkyl, adamantyl, norbornyl, fluorinatedalkyl and heterocycle; wherein the aryl, aralkyl or heterocycle may beoptionally substituted with one or more substituents independentlyselected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino,mono-or di-substituted amino, cyano or nitro; where R^(A) and R^(B) areindependently selected from the group consisting of hydrogen, —R, —COOR,—COR, —SO₂R, —SOR and —CONR^(C)R^(D) and

where R^(C) is selected from the group consisting of hydrogen, alkyl,aryl, aralkyl, cycloalkyl, fluorinated alkyl and heterocycle; whereinthe aryl, aralkyl or heterocycle may be optionally substituted with oneor more substituents independently selected from halogen, hydroxy,alkyl, halogenated alkyl, alkoxy, amino, mono-or di-substituted amino,cyano or nitro; or are joined together to form a 4 to 8 memberedheterocyclyl ring structure; which method comprises reacting a compoundof formula (III)

with a compound of formula (IV)

wherein A is selected from F, Cl, Br or OC(O)-t-butyl, and wherein V isa sterically hindered group, in a non-protic solvent; and then reactingwith a compound of formula (VIII) R⁵—N═C═O   (VIII) wherein R⁵ is aspreviously defined, to yield the compound of formula (Id).
 30. A methodfor preparing compounds of the formula (IId)

wherein X is selected from the group consisting of NH, NR^(A) and S;

represents a 9 membered ring structure, wherein the five memberedportion of the ring structure

is aromatic and the six membered portion of the ring structure

is saturated, partially unsaturated, or aromatic; wherein the 5 memberedportion of the ring structure is optionally substituted with one to twosubstituents independently selected from the group consisting ofhalogen, hydroxy, alkyl, alkenyl, halogenated alkyl, cycloalkyl, alkoxy,aryl, aralkyl, heterocyclyl, amino, mono-or di-substituted amino, cyano,nitro, —COOR, —COR, —SO₂R and —CONR^(B)R^(C); wherein the aminesubstituents are independently selected from alkyl, cycloalkyl, aryl oraralkyl; wherein the cycloalkyl, aryl or heterocyclyl may be furtheroptionally substituted with one or more substituent is independentlyselected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino,mono-or di-substituted amino, cyano or nitro; wherein the 6-memberedportion of the ring structure may further optionally containing one tofour additional heteroatoms selected from the group consisting of N, Oand S; wherein the 6-membered portion of the ring structure may furtherbe optionally substituted with one to four substituents independentlyselected from the group consisting of halogen, hydroxy, alkyl,halogenated alkyl, cycloalkyl, alkoxy, aryl, aralkyl, heterocyclyl,amino, mono-or di-substituted amino, cyano, nitro, —COOR, —COR, —SO₂Rand —CONR^(B)R^(C); wherein the amine substituents are independentlyselected from alkyl, cycloalkyl, aryl or aralkyl; wherein thecycloalkyl, aryl or heterocyclyl may be further optionally substitutedwith one or more substituent independently selected from halogen,hydroxy, alkyl, halogenated alkyl, alkoxy, amino, mono-or di-substitutedamino, cyano or nitro; V is selected from the group consisting oft-butyl, adamantyl, —N(alkyl)₂, —N(aryl)₂, 2,6,-dimethylphenyl,2,6-disubstituted phenyl (wherein the substituents are selected fromhalogen, alkyl or alkoxy), —O—t-butyl, —O—i-propyl and —O— adamantyl; R⁵is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl,cycloalkyl, fluorinated alkyl and heterocyclyl; wherein the aryl,aralkyl or heterocyclyl may be optionally substituted with one or moresubstituents independently selected from halogen, hydroxy, alkyl,halogenated alkyl, alkoxy, amino, mono-or di-substituted amino, cyano ornitro; where R is selected from the group consisting of alkyl, aryl,aralkyl, cycloalkyl, adamantyl, norbornyl, fluorinated alkyl andheterocycle; wherein the aryl, aralkyl or heterocycle may be optionallysubstituted with one or more substituents independently selected fromhalogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino, mono-ordi-substituted amino, cyano or nitro; where R^(A) and R^(B) areindependently selected from the group consisting of hydrogen, —R, —COOR,—COR, —SO₂R, —SOR and —CONR^(C)R^(D) and

where R^(C) is selected from the group consisting of hydrogen, alkyl,aryl, aralkyl, cycloalkyl, fluorinated alkyl and heterocycle; whereinthe aryl, aralkyl or heterocycle may be optionally substituted with oneor more substituents independently selected from halogen, hydroxy,alkyl, halogenated alkyl, alkoxy, amino, mono-or di-substituted amino,cyano or nitro; or are joined together to form a 4 to 8 memberedheterocyclyl ring structure; which method comprises reacting a compoundof formula (VII)

with a compound of formula (IV)

wherein A is selected from F, Cl, Br or OC(O)-t-butyl, and wherein V isa sterically hindered group, in a non-protic solvent; and then reactingwith a compound of formula (VIII) R⁵—N═C═O   (VIII) wherein R⁵ is aspreviously defined, to yield the compound of formula (Id).